System, method and apparatus to enhance privacy and enable broad sharing of bioinformatic data

ABSTRACT

A system, method and apparatus for enabling individuals to determine their sharing, privacy, and data access preferences and conditions for disclosure of bioinformatic data, including whole genome sequence data over a network. In combination with a privacy preferences repository and policy repository for expressing legal and institutional criteria for accessing such information, a private access bureau enables such privacy requirements to be addressed while simultaneously enabling broad sharing of such data by and with properly authorized parties or applications. Through the use of various forms of metadata, encryption, and globally unique IDs that accompany such data elements, discrete segments of said data can be queried; and where permissible discovered, accessed, analyzed, viewed, linked with other health data and contact details, used, and/or exported based on pertinent privacy laws, institutional policies, and the individual&#39;s preferences that are associated with, and dynamically controlled through, an intuitive user interface.

TECHNICAL FIELD

This disclosure relates to segmenting and controlling the flow of a widevariety of sensitive data including bioinformatic information over anetwork such as the Internet or an intranet, in communication with userpreference repositories and policy repositories to enhance privacyprotections for, and simultaneously to enable broad sharing and analysisof, such information.

BACKGROUND

Recent advances in Whole Genome Sequencing (WGS) and Next-GenerationSequencing (NGS) have dramatically improved the speed and throughput,reduced the costs, and improved the accuracy and richness of detailaccessible through genetic sequencing. In just over a decade sincecompleting (in 2003) the first full sequencing of a human genome at thecost of over a billion dollars, the cost of WGS dropped in 2014, withthe release of Illumina's new HiSeq X™ system, to $1,000 for 30×coverage of a human genome, inclusive of instrument depreciation,sequencing consumables, DNA extraction, library preparation, andestimated labor for a typical high-throughput genomics laboratory.Reductions in cost and improvements in quality are forecast to continue,prompting a number of observers to predict that conducting a genetictest will in the future become as common as a urinalysis and blood testare today in the practice of medicine.

In order to increase the predictive value of such tests, and to discovernew and better ways to improve health outcomes, diagnose and relievechronic disease, and treat illness, there exists widespread interest incorrelating longitudinal clinical detail, lifestyle choices,environmental exposure, and phenotypic information with the results fromgenomic sequencing. Researchers in public health agencies, academic, andcommercial settings such as pharmaceutical firms, insurers, andgovernments are among the many parties located in countries all aroundthe world who foresee the prospect for considerable benefit inaccelerating innovation, reducing costs, and improving both theirservices and their profitability, through improved access to and use ofsuch information.

The willingness to make ones' information broadly accessible is alsorelatively common among individuals who are affected by some complexconditions for which traditional diagnostic procedures and treatmentmodalities are today inadequate, their family members, and affinitygroups which represent them. In addition to the general notion thatgenerally healthy medical altruists feel about being among the first todo something new and the prospect of advancing scientific discovery,individuals who are affected by disease and their loved ones frequentlyare motivated by the hope that genetic analysis will be useful inascertaining the source of unexplained symptoms, and thereby useful inreducing the “diagnostic odyssey” that is frequently experienced bypatients with rare or exceedingly complex conditions, as well as inhelping to identify more or less beneficial treatment regimes for theirparticular conditions. Indeed, such benefits are beginning to bedemonstrated in various sub-specialties, including oncology for someforms of cancer, pediatric neurology, and with respect to some heritabledisorders. And yet, proponents of the science—of which there aremany—believe we have barely scratched the surface and that thecontributions of these early adopters must be combined within hundredsof thousands, perhaps millions of others' equally detailed informationto discover the playbook this blueprint contains.

As the price for WGS continues to decline and number of proven uses forexome testing and NGS increase, these early applications to help advanceresearch and reduce the diagnostic odyssey for some rare conditions areanticipated to pave the way to so called “precision medicine” where theselection, dosage, and specific titration of a medication or treatmentis custom tailored to what will be most effective to the individualpatient. Getting to this point will require better ways to rapidlyidentify the appropriate (and increasingly, genetically appropriate)research cohorts for clinical trials, and once a personalized treatmenthas been sufficiently demonstrated as being efficacious, institutingfaster and more cost effective ways to analyze the results of NGS andderive such conclusions, as well as improved means to disseminate suchresults broadly to treating professionals so that recommendations can betimely employed at the point of care or dispensing medication, and beingappropriately remunerated.

Additionally, the trends of increased speed, ease of use, and rapidlydeclining cost of acquiring, analyzing, storing, and disseminating NGSdata have greatly enhanced the prospects for broad “populationgenetics.” Thus, what less than a decade ago would have been aprohibitively expensive and time-consuming process, has moved to theverge of being widespread, with major projects already announced and/orunderway in a number of countries around the world. One example of theseis the initiative by Genomics England to provide whole-genome sequencingby 2018 for up to 100,000 patients with genetically driven disease inthe UK. Other significant initiatives are being considered literally allaround the world, as research scientists, political leaders, commercialinterests, and affected individuals and their families seek to take partin, and derive benefit from the explosive field.

By using data from these sorts of large population-wide initiatives(alone and in combination with information derived from clinicalencounters and initiatives taking place in other countries), researchershope to better correlate genotype, phenotype, lifestyle, andenvironmental exposure, and from such larger data sets and betteranalyzed and documented information within them, hope to accelerate andimprove overall health outcomes and simultaneously reduce health carecosts. Among the objectives that are frequently mentioned are reducingserious problems through better and more widespread carrier analyses,and assuring more timely interventions in the case of serious illnessthrough non-invasive prenatal testing (NIPT), more comprehensive newbornscreening panels, and tests conducted on DNA fragments ascertained incirculating blood that might someday become part of standard clinicalprotocols for preventative healthcare.

Some experts go so far as to express optimism that as the number ofaccessible genome sequences increases, and are subjected to analysis andthe data shared, that researchers (and eventually practicing physicians)will increasingly be able to proceed from genotype to phenotype (ratherthan, as has heretofore commonly been the case, from phenotype togenotype) in developing and employing interventions that are of benefitto individuals with a predisposition to particular health problems.Others are optimistic this will result in identifying uncommonindividuals—what some have called “accidents of nature”—who are, due tosome yet-to-be-discovered mechanism, “protected” from adverse phenotypicconsequences of otherwise problematic genetic variants, and from whichobservations and analyses, new treatments may be developed in thefuture.

The decline in cost and simultaneous gains in the speed and accuracy ofNGS have to date exceeded the levels of improvement forecast by Moore'sLaw. And as experts look to the future, there is optimism that the fieldwill similarly experience the kinds of exponential increase (n² or n×logn, etc) in overall value predicted by Metcalf's Law (or one of itscorollaries) as the number of users sharing information as part of anetwork increases. Such gains inherently depend on the extent to whichhigher levels of participation in data sharing are practiced. And yet itis widely understood that openly sharing genomic information(particularly when such information is combined with detailed familyhealth history) is not embraced by everyone. In point of fact, thereexists substantial concern—and given the nature of genomic information,perhaps more so than any other form of health data—that such sharing bedone with complete knowledge of the risks this entails and greaterprotections against misuse of the information that could be detrimentalto the individual (as well, conceivably, as non-consenting bloodrelatives of the individual) from which the information is derived.

A 2009 article by Duke University professor and bioethics policyresearcher, Misha Angrist, describes the vulnerability of genomic data,and its sensitivity to changing conditions due to continually improvingdata analysis technologies. Angrist observes:

-   -   Participant privacy and confidentiality considerations are        mainstays of human subjects research involving genetics and        genomics. Perhaps the most salient illustration of this can be        found in the [ ] turbulence surrounding the NIH policy regarding        genome-wide association studies (GWAS) data. In implementing its        data-sharing policy in 2007, the NIH's expectation was that        unless they could offer a compelling reason not to, NIH grantees        would share their human genomic data with other investigators.        It was also made clear that the decision to share or not to        share could have tangible consequences: ‘The ability to share,        and the richness of the data for maximizing the usefulness of        future research, may be considered . . . as part of award        decisions’.

In 2011, the National Research Council under a contract between theNational Academy of Sciences and the NIH convened a prestigious group ofexperts to consider the requirements and impediments of developing thesort of “Knowledge Network” required for advancing precision medicine.The final report, entitled “Toward Precision Medicine: Building aKnowledge Network for Biomedical Research and a New Taxonomy of Disease”identified privacy issues as a material impediment, stating in part:

-   -   The HIPAA required the federal government to develop regulations        for protecting the privacy of personal health information. The        HIPAA privacy regulations, which are intended to protect patient        privacy, inhibit research that requires widespread sharing and        multi-purpose use of data on individual patients in several ways        (IOM 2009): First, rich molecular data about an individual        (particularly whole-genome sequencing) could be considered a        unique biological identifier under HIPAA, even if overt        identifiers are removed. Although a waiver of authorization to        use identifiable health information may be granted under certain        circumstances, many health-care organizations are reluctant to        participate. Secondly, because HIPAA does not allow        authorization for unspecified future research or for several        projects at one time, authorization must be given for each        specific use of patient data. Thirdly, requirements for        “accounting” to patients for research uses of data are        burdensome and discourage data sharing. These regulations are        strong deterrents to [precision medicine initiatives].

On Aug. 27, 2014, the National Institutes of Health (NIH) issued a newpolicy regarding genomic data sharing (seehttp://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html,accessed online on Jan. 19, 2015). The new policy (GDS Policy) providedan attempt to balance the benefit to be derived from more broadlysharing of this information; and yet as a prerequisite to such use, thedecision to require more extensive participant consent that someresearchers and institutions had treated as being unnecessary. The NIH'snew GDS Policy establishes an expectation that all investigatorsgenerating genomic data should seek consent from participants for futureresearch uses that enable “the broadest possible sharing to the greatestextent possible [ . . . including] for future unspecified use of theirgenomic data.” (Emphasis added) And while the new policy expresslyacknowledges that current forms of consent for future research uses andbroad sharing of this data may not be adequate or obtainable in allcircumstances, the GDS Policy indicates that the policy applies to allresearch regardless of whether it occurs in a clinical setting orinvolves data generated from deceased individuals; and says that “[t]hebreadth of the sharing permitted by the consent may be taken intoconsideration during program priority review by the ICs[Institute/Centers].”

As explained on the Department of Health and Human Services' website,“The HIPAA Privacy Rule provides a Federal floor of privacy protectionsfor individuals' individually identifiable health information . . . .State laws that are contrary to the Privacy Rule are preempted by theFederal requirements, unless [ . . . ] the State law [ ] relates to theprivacy of individually identifiable health information and providesgreater privacy protections or privacy rights with respect to suchinformation.” A similar deference to state law is contained in theCommon Rule, which addresses data sharing in a research rather thanclinical context, and that expressly states that “[the Rule] does notaffect any State or local laws or regulations which may otherwise beapplicable and which provide additional protections for human subjects.”Moreover, the Common Rule expressly recognizes additional staterequirements for informed consent, stating: “The informed consentrequirements in this policy are not intended to preempt any applicableFederal, State, or local laws which require additional information to bedisclosed in order for informed consent to be legally effective.”Identical language appears in the regulations of the Food and DrugAdministration.

As one example of the kinds of challenges that such preemptive rightspresent, in the State of New York, the legislature enacted a datasharing law specifically to protect the privacy of genomic information.Under the New York State Civil Rights Law, “all records, findings andresults of any genetic test” may not be disclosed without the writteninformed consent of the person to whom the test relates, and the subjectof the test must specifically identify any person or organizations towhom such information may be released. Referring to N.Y. Civ. Rights Law§ 79-I(2)(a). Moreover, the statute provides that “any furtherdisclosure of genetic test results to persons or organizations not namedon the informed consent require the further informed consent of thesubject of the test. Referring to § 79-I(2)(d). (Emphasis added)

Some individuals are fearful that WGS information may be used for racialdiscrimination, the denial of services due to genetic predispositions,and the disclosure of intimate familial relationships such asnon-paternity. While some view such risks as being moot in contemporarysociety, others see these as palpable risks and cite to recent examplesof capital punishment for infidelity in the Middle East, and ethniccleansing in Eastern Europe, Africa and India, as palpable grounds forconcern. Experts also warn that risks of retribution and adverseconsequences conceivably could extend well beyond the person who isactually consented to being tested, including all of that individual'sblood relatives such as siblings, children and grandchildren.Undoubtedly, such concerns arouse strong sentiments and, at times, quiteextreme (and potentially counter-productive) reactions. Citing toconcerns over the lack of adequate protections against misuse, millionsof dried blood spots collected over a period of several decades throughthe nation's newborn screening program were permanently destroyed inseveral states as the result of court proceedings and lawsuits initiatedby activists. Given the forensic value of genetic information (and theprospect that information acquired in a health context could make itsway to law enforcement), concerns are often greater among ethnic andminority religious groups that have historically been the subject ofdiscrimination.

Even where individuals are willing to share their information, there arepresently a number of practical challenges. Current models forprotecting health care data generally impose a legal obligation on theparty receiving and/or holding the information (variously hereinreferred to as the “data holder”, “resource holder” or “record holder”,which terms are used interchangeably) to protect the informationentrusted to them by patients in the clinical context, or subjects inthe research context. This focus is codified in the legal and ethicalframeworks that govern clinical practice and research activities in mostcountries, and impose financial and reputational penalties for violatingsuch rules. The obligation does not extend to entities to which acovered entity or business associate might disclose personal healthinformation (i.e., there is a lack of persistence of these privacyobligations). As a result, each entity with which the individualinteracts (each doctor, hospital, insurance carrier, lab, pharmacy,etc.) effectively controls access to a different slice (both insubstance and time) of a person's information. In turn, this leads todata “silos” because each institution separately administers only thedata it receives and/or generates; and sharing this information broadlyis not only challenging from a privacy perspective, but also contrary tothe present incentive model in which control over large quantities ofhealth data frequently has both direct and indirect economic andcompetitive value.

Privacy law differs substantially between the United States and Europe,beginning in its underlying philosophy. Generally speaking, in theUnited States, privacy laws focus on redressing consumer harm andattempting to balance privacy with efficient commercial transactions andthe public interest; whereas in the European Union, privacy is treatedas a “fundamental right” that can take precedence over other interests.In the United States “personally identifiable information” (PII)involves multiple and at times inconsistent definitions of PII that areoften particularly narrow; whereas in EU, PII encompasses allinformation identifiable to a person.

In Europe, the data protection law is currently under review to takeinto account important considerations such as globalization andtechnological developments like social networks and cloud computing.Presently, it is expected to result in adoption of the General DataProtection Regulation (GDPR) in 2015, with enforcement expectedbeginning in 2017. While still under discussion, it seems likely thatthe GDPR will contain a number of aspects that create challenges fortraditional biobanking activity and other bioinformatic data acquiredwith prospective approvals that are not explicit as to the intendedpurpose, recipients, third-country transfers, and type of data andconsequences of processing at the time such consent is sought. Andmoreover, even the prospect that this will be the case has a chillingeffect on development activity with regard to any form of traditionalconsent under the current state of the art. For a review, see “Openconsent, biobanking and data protection law: Can open consent be‘informed’ under the forthcoming data protection regulation?” (availableonline at http://www.isspjournal.com/content/pdf/s40504-014-0020-9.pdf,accessed Mar. 2, 2015)

Similar to the challenges of variability of laws between states in theU.S., the disharmony in legislation between different countries carriesrepercussions for businesses attempt to function across disparate rulesregimes. While popular and trade media has focused on the criticalnature of this with respect to the Safe Harbor Rules, there existpotentially formidable challenges for medical researchers wishing toundertake broad comparative studies of bioinformatic data, and who arecompelled to navigate multiple laws and regulations (each in flux fromtime-to-time) with different standards for access to and use of data.

Privacy challenges surrounding the research uses of clinical data havelong been recognized; and the advent of genetic information has furtherexacerbated such concerns. WGS data is itself a “biometricidentifier”—one of the 18 data elements the HIPAA Privacy Rule requiresto be removed in order to render clinical data “de-identified”. Lawenforcement agencies utilize genetic data, and there have been strikingexamples of how easy it is to re-identify individuals using just a fewelements of genetic information in combination with readily-accessiblepublic data sets. As a consequence, clinical and research oversightbodies such as Institutional Review Boards (IRBs) and medical ethicscommittees—which generally focus on “protecting patients” by means ofde-identifying and disconnecting data sets from patient identifiers asmuch as possible—are understandably confused about how to regulategenetic data sharing and genomic tests that rely upon access to suchinformation.

Even in the clinical context, where applicable laws concerningtreatment-related uses of information permit including NGS results inthe electronic health record, significant problems are beingencountered. Clinicians are increasingly concerned that if a specificvariant is revealed—but that was not part of the intended use of theorder and yet that has clinical significance (even later on)—they may beliable for that finding should it manifest in the tested individual inthe future. Recent guidance released by the FDA and OHRP (Office ofHuman Rights Protection) further muddy the waters and limit innovationand novel research. Some experts question if including the WGS in thehealth record obligates a provider to take it into account (for example,when prescribing medications). Absent sophisticated decision supportsystems (DSS) to alert practitioners to the contents and potentialapplicability of such data, doing so could add materially to the timerequired to see patients, and highlight the lack of adequate training ofmost providers to properly assess and employ such information. In a riskadverse, litigious climate with the inability to better predictregulatory and judicial direction (let alone the speed of change takingplace in medical knowledge in genomics, pharmacogenomics, and relatedfields), the “prudent” course is frequently to exclude the WGS from thepatient's record, and to treat the information exceptionally.

In February 2009, the European Journal of Human Genetics published anarticle describing concerns about privacy, confidentiality,discriminatory and defamatory use of genetic data, and the complexitiesof informed consent for both research participants and their closegenetic relatives in the era of personalized genomics due to, amongother things, the potential for indirect estimation of genetic risk inan otherwise fully disclosed genome sequence. The authors described thatthey contacted Dr. Watson and his colleagues in December 2007 andFebruary 2008 to “inform them of the possibility of inferring his riskfor LOAD conveyed by APOE risk alleles using surrounding SNP data. As aconsequence, the online James Watson Genome Browser (JWGB) has nominallyremoved all data from the 2-Mb region surrounding APOE.” See Dale Nyholtet al. On Jim Watson's APOE status: Genetic information is hard to hidein European Journal of Human Genetics, February 2009, 17(2): 147-149(Accessed online on Jan. 19, 2015 athttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986051/).

There are also a number of very practical considerations involved. Theaverage raw genetic sequence file contains several hundred gigabytes ofdata, which must be processed to make sense of the data and identify thesubset of functionally important variants. This process includesmapping, aligning, de-duplicating, merging, and comparing the observedvariants to a reference genomic sequence, and from which annotation andmedical recommendations may be derived. Whereas historically,brute-force computing has been employed to organize and make thesequenced data useful, this is both costly and slow, even withhigh-speed cloud-based computing centers.

Various methods have been proposed through which to expedite and reducethe cost of this pre-analytic step, with the prospect today of reducingthe overall time required by handling the processing using a specializedintegrated circuit chip and/or through gains in the speed of processingthe data using software that is in turn realizing the benefit of Moore'sLaw sorts of efficiencies. While these recent innovations make itpossible to now produce a file of several hundred megabytes in size thatserves as the starting point for most variant analyses and diagnosis ortreatment recommendations in a much shorter period, there remains acritical limiting factor in both cost and time required to analyze theraw sequence data.

A number of proprietary and open source based software tools have beenproposed and are increasingly being employed through which to transformthe data in the variant file or its equivalent from an output list ofvariants to an interpretation of the sequencing data. Generallyspeaking, these tools perform gene, region and filter based analyses andannotations, pull from reference data by numerous published andproprietary systems and annotations to identify individual variants,prioritize the identification of disease genes in an individual, familyor population, and offer the knowledge of corresponding clinicalimplications and/or treatment recommendations in a summary report.

While privacy of the information is widely understood as being ofcritical importance, to date, relatively little has been produced interms of privacy protective technologies. On the contrary, untilrelatively recently, most practitioners within the field have generallyworked under the assumption that the biological samples and genomicinformation could be “de-identified” by removing references to theindividual's name or any one or more of approximately two dozenexpressly identifying characteristics (e.g., address, phone number,social security number, etc). However, relatively recently through thework of several leading researchers, this presumption has beenirrefutably found to be erroneous.

Confounding the foregoing problems, almost all data sharing protocolschose a single point solution in what is commonly presented simply asthe dichotomous option to either ‘opt in’ or ‘opt out’ of participating.Even in the few systems that move beyond this binary selection, a menuof narrow, static options is commonly offered. These consent systemsgenerally produce fixed and unalterable choices, unmindful that personaland public context is highly changeable even over short periods, anddevoid of the other essential elements that are addressed in the systemand method disclosed in Applicant's U.S. Pat. No. 9,032,544 (System andmethod for controlling communication of private information on anetwork), herein the '544 patent, the teachings of which areincorporated herein by reference.

Genomic data is considered by many, if not most, people to be“intrinsically private” (as has been held by the European Court of HumanRights, or ECtHR) inasmuch as a massive number of traits can potentiallybe analyzed from any given sample. These include physical attributes(such as blue eyes, brown hair, detached ear lobes, etc), as well ascurrent or future medical (has condition A, does not have condition A,is X % likely to contract condition A in the future) and/or socialstatus (has genetic predisposition toward social characteristic S), andmay be held in common with others (for example blood relatives).Moreover the content and amount of information that can be extractedfrom the genome is increasing at an exceptionally fast pace, such thatall anyone can predict with relative assurance at this point is that thecontent, form and specificity of information about an individual thatcan be extracted from a sample will be greater in the future than it iscurrently. The foregoing has led the ECtHR to opine that “the Courtcannot discount the possibility that in the future the private-lifeinterests bound up in genetic information may be adversely affected innovel ways or in a manner which cannot be anticipated with precisiontoday.”

Although a modest number of genes are required for lead validation andpharmaceutical genotyping, a large number of compounds and patientsamples are required to obtain meaningful statistics to support thederived linkage information. Similarly, although DNA diagnostics andclinical genotyping commonly require only a modest number of genes,identification and refinement of these techniques relies upon very largesample populations. And whereas high levels of confidence in diagnosingmutation and infectious diseases rely on a modest number of genes orSNPs, a great number of individual samples must be tested and analyzedto achieve widespread application. Whereas ultimately, clinicalgenotyping to support personalized medicine will likely require verysmall gene sets to indicate such attributes as toxicological andtreatment response, high throughput must be achieved in order for thisto be meaningful to large populations. An improved means to addressprivacy considerations and build trust, and that overcomes thelimitations in the current approaches to privacy and security iscritical to attaining such goals.

SUMMARY

This disclosure provides a system, method, and optional apparatus forovercoming the limitations described in the Background discussion;enabling on the one hand, substantially greater protections for theprivacy of bioinformatic data including whole genome sequencing data,while simultaneously broadening access to such data and increasing itsusefulness in clinical, diagnostic, research and other market contexts.Contrasted with existing methods for protecting the privacy of suchsensitive data (which dramatically reduce the accessibility and/ordegrade the data's utility) and traditional methods for making theinformation more accessible and its uses (which are accompanied by anincrease in privacy risk), the disclosed system, method and apparatusrepresent a material improvement over the current state of the art.

These improvements accrue through the disclosed system and method ofsegmenting and controlling the flow of the data over a network such asthe Internet or an intranet, in communication with user preferencerepositories and policy repositories to enhance privacy protections for,and simultaneously to enable broad sharing, analysis and use of, suchinformation. The system and method may be performed using speciallyprogrammed computer processors or, in one preferred embodiment, may beexecuted through use of a hardware processing platform, such as anintegrated circuit, to locate key regions within such data, to assignmetadata and index such information, and to implement privacy-awareaccess controls with respect thereto. In each case, such steps can beemployed either as a standalone process, or preferably as an integralpart of performing one or more functions that are already required inanalyzing and processing such data. These steps may be performed locally(meaning at the same location where the sequence is produced), or in thecloud or other virtual private network. And in one optional preferredembodiment, some or conceivably all of these steps may be performedusing homomorphic encryption to protect the content about which thefunction pertains while simultaneously enabling the functional step tobe processed and a meaningful result provided.

In the one preferred embodiment, the disclosed preparation andspecialized processing enables said data set to be incorporated in asearchable public index from which it can be queried, accessed, used,and/or made accessible to being shared with others pursuant to robustprivacy protective protocols that optionally accompany such dataelements. The preparation preferably also enables maintaining dataprovenance and audit reports, eliminating undesired duplication ofrecords, and for verifying downstream conduct of those who receiveaccess to the data, while simultaneously enabling the parties orentities that are the source or author of the privacy directives (ortheir representatives, collectively herein “grantors”) to change theirdirection over time, as circumstances, associated consequences, andperceived needs arise. In yet another one preferred embodiment, thedisclosed system and method enables calculation and distribution offees, attribution, and other value produced through sharing suchinformation with others, as and when permissible in accordance with suchprivacy protocols.

Although these steps may be performed through specialized software, inone preferred embodiment, such processing is performed using a hardwareaccelerator, such as an integrated circuit, to enable the steps to beperformed in one or more hardwired digital logic circuits that may beinterconnected by a plurality of physical electrical interconnects, andthat can be arranged as a set of processing engines, wherein eachprocessing engine is capable of being configured to perform one or moresteps in segmenting, assigning various metadata elements, indexing,compressing, encrypting, and assigning one or more codes that associatedirectly or indirectly to the then current instantiation of the privacydirectives (in law, local institutional policy and patient privacypreferences) governing such data element.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1, consisting of three subparts, illustrates the major stepsinvolved in practicing the invention, including in subpart 1(A) thephases of information processing that are currently involved inproducing an individual digital genetic code from a sample andidentifying variants therein, and in subparts 1(B) and 1(C), theadditional steps involved in practicing the system and method disclosedherein in accordance with the teachings of the invention, includingthrough use of the apparatus;

FIG. 2, consisting of subparts 2(A), 2(B), 2(C), 2(D) and 2(E), is aseries of simplified illustrations showing the effect of segmenting thegenome at various levels of granularity in accordance with the teachingsof the invention, and illustrating the effect of such various levels ofaccess controls;

FIG. 3 is a system block flow diagram for segmenting, assigningmetadata, indexing, compressing, encrypting, and associating one or moreunique codes that associate directly or indirectly to the then currentinstantiation of the privacy directives governing access to such dataelement at the time access thereto is sought by a data seeker, inaccordance with an illustrative embodiment of the invention;

FIG. 4 is a simplified illustration showing one preferred arrangement ofsuch one or more indexable metadata, encryption, and assignment ofglobally unique identifiers for such data and metadata elements, inaccordance with an illustrative embodiment of the invention;

FIG. 5, consisting of subparts 5(A)-5(D), is a series of drawingsshowing an ontology for expressing privacy directives associated withsuch data and various levels of metadata respecting the granularsegments of bioinformatic data in accordance with the teachings of theinvention, and several examples illustrating its use;

FIG. 6 is a sequence diagram showing the interaction between a partyrequesting data from a privacy-enabled system, the private accessbureau, and the participant for controlling the release of informationby an enterprise or privacy-enabled device in accordance with theteachings of the invention; and

FIG. 7, consisting of subparts 7(A)-7(I), is a series of illustrativeuser interface designs for intuitively establishing preferencesregarding the right to analyze, discover, view, use, export, and linkbioinformatic data including genomic data with other health informationand contact details for the individual to whom each of such element(s)pertain.

DETAILED DESCRIPTION

Detailed embodiments of the present invention are disclosed herein,however, it is to be understood that the disclosed embodiments aremerely exemplary of the invention, which may be embodied in variousforms. Therefore, specific functional details disclosed herein are notto be interpreted as limiting, but merely as a basis for the claims andas a representative basis for teaching one skilled in the art tovariously employ the present invention.

In an illustrative embodiment of the invention that is described hereinwith reference to FIG. 1, subpart 1(A) illustrates the current state ofthe art involved in generating digital genetic code for an individualand determining the variants present in that individual's genetic makeupcompared with a reference genome. As shown in FIG. 1(A), the processbegins with collection of a biological sample 101, consisting of blood(as shown for illustrative purposes), or alternatively any number ofacceptable materials such as saliva, hair, tissue, or the like.

This sample is then prepared using established laboratory techniques andloaded into a sequencing device, 102. In a non-limiting example, FIG.1(A) shows use of Illumina's HiSeq® X device, which was released inFebruary 2014 and advertised as being the world's first sequencingplatform to break the $1000 barrier for 30× coverage of a human genome.Persons of ordinary skill in the art will be aware there are a number ofcompeting devices; Illumina itself offers a line of machines ofdifferent speeds, cost and throughput capacity; and there are indevelopment next-generation machines that may be used in the future. Anysuch machines performing the function of converting an individual'sgenetic code into machine-readable digital code, 103, are suited toemploy the practices of this invention. Similarly, a wide variety ofmachines and other devices that produce other types of bioinformaticdata may employ the teachings of the invention and are thus encompassedby this illustrative case; and the output thereof is expressly intendedwithin the reference to machine-readable digital code 103.

In the present example, such machine-readable code is saved to a FASTQfile 104, whose size is commonly in the range of several hundredgigabytes or larger depending on the levels of coverage applied. Theidentification of a particular file format is intended solely forillustrative and not limiting purposes, as this disclosure is intendedas broadly as possible to pertain to any file or intermediate workproduct (such as a FASTA, BCL, BAM or SAM file, etc.) comprising thedata 103 educed during the process of sequencing sample 101, now or inthe future.

During the next processing phase, such generated digital genetic code isused in determining the individual's genetic makeup, e.g., indetermining the individual's genomic nucleotide sequence. Under thecurrent state of the art, during the processing that typically comprisesthis phase, the raw data contained in the FASTQ file 104 is sent usingknown conventional means 105 for file access (if the work will beperformed locally) or transport (if, for example, the processing will beperformed at a different location or using cloud-based processors) toone or more computers 106(A) or to a hardware platform such as aspecially designed integrated circuit chip 106(B).

The data from the millions of reads stored in file 104 is then mappedand aligned, sorted, and de-duplicated. Rectangular boxes 107, 108 and109, respectively, represent these steps. As part of sorting, arrangingand/or de-duplicating the data so that it appears in the properalignment, or after the data is arranged to be in the proper alignmentthrough such steps, the processing also identifies differences (i.e.,variants) between the assembled genome of the individual and a referencegenome. This process is represented by rectangular box 110, entitled“variant calling”, and identifies how the individual's genetic makeupdiffers from that of the referent(s). Persons of ordinary skill in theart will understand that this description of the prior art represents asimplified explanation that highlights the major steps involved in suchprocessing of the raw data that will be useful in this disclosure, andthat there are other functions such as local realignment, duplicatemarking, base quality score recalibration, compression, decompression,and other functions that may take place as part of these steps andwhich, depending on the methods and objectives of the sponsor of suchwork may take place during the course of such intermediate processing.

Under the prior art, once the variant calling process is completed(inclusive of such additional functions), the data is written to a file,indicated by arrow 111, in “Variant Calling Format”, to produce VCFfile, 112, employing a standard that lists and annotates the entirecollection of human variants. The VCF in its basic form is a list oflocations of variants and their type: e.g., chromosome 3, at position X,an “A” is substituted for a “T”, etc. As the field develops, such filemay be modified, supplemented or replaced with one or more other formatsthat incorporate additional aspects of the genome. For the purposes ofthis disclosure, any such file that serves as a predicate for analysisand so called tertiary processing of such information is intended to beencompassed within the meaning of VCF file 112, as used herein.

As previously noted, this intermediate processing may be performed usingspecialized software such as Illumina's HiSeq® Analysis Software (HAS)or other open source and/or proprietary software running on computerserver(s) to provide a full spectrum of variant types. Such variantsinclude single nucleotide variants (SNVs), indels (inversions anddeletions), structural variants (SVs), and copy number variants (CNVs).Depending on the sequencing equipment and the preferences of thelaboratory or sponsor for the work, this processing may take placewithin the sequencer equipment itself, or may take place using computerhardware that is located on-site, computers located at another location,or within a cloud-computing environment such as Amazon Web Services,Google's Genomics platform, Illumina's BaseSpace® genomicscloud-computing environment, or the like. All of these alternative meansare represented by servers 106(A) shown in FIG. 1(A).

Various methods have been proposed through which to expedite and reducethe cost of these pre-analytic steps, including through optimizedpipeline software and the prospect of reducing the overall time requiredby handling the processing using a specialized integrated circuit chip.U.S. patent application Ser. No. 14/180,248 (Bio-informatics systems,apparatuses, and methods executed on an integrated circuit processingplatform), filed on Feb. 13, 2014, by Pieter Van Rooyen et al., andassigned to Edico Genome, Inc. (herein the '248 application), disclosesprocessing such data within a hardware platform such as a speciallydesigned integrated circuit containing technologies for performing oneor more of such mapping, aligning, sorting, local realignment, duplicatemarking, base quality score recalibration, variant calling, compression,and/or decompression functions. Such hardware is represented by computercard and specially programmed integrated circuit chip 106(b).

The '248 application also describes that in various embodiments, abioinformatics processing regime may be employed within such apparatusfor the purpose of creating one or more masks, such as a genomereference mask, a default mask, a disease mask, and/or an iterativefeedback mask, that may be added to the mapper and/or aligner, e.g.,along with a reference, wherein the mask set is configured so as toidentify a particular area or object of interest. And as describedtherein, in one embodiment of the methods and apparatuses disclosed, themask set is configured so as to identify areas of high importance and/orrelevance, e.g., to the practitioner or subject, and/or so as toidentify areas having increased susceptibility to errors.

It is well understood that once a VCF file has been generated, the datait contains may be subjected to various forms of tertiary processing andanalyses to interrogate, interpret, and draw conclusions concerning theindividual to whom such digital code pertains. Such tertiary analysesmay be performed for a variety of useful purposes, including assistingin diagnosis, targeting treatment (perhaps even in advance of anyadverse health problems), advancing research, and for forensic uses. Andyet, like most powerful tools, such tertiary analyses also can bemisused and/or abused, for example as a means to re-identify data thatwas intended to be kept anonymous, as the basis for variousdiscriminatory practices, stigmatization, termination of otherwiseviable fetuses, and at its extreme, retribution, eugenics and ethniccleansing.

Given the potential both for beneficial uses as well as highlydetrimental misuse, the importance of ethical uses of such informationhas been emphasized since the inception of the genomics age. Ethicistshave long appreciated that the widespread ability to uncover geneticpredispositions and one's very identity through analysis of ones genomicsequence has significant implications for individuals, their families,and society as a whole. Because genes are considered highly significant(and in some cases central) in determining who a person is and whatchallenges or strengths he or she is likely to exhibit, informationabout genetic mutations may cause a person to change his or herself-image, and may alter the way others treat that person.

The prospect for such information to be misused or misunderstood haslead to legal and ethical expectations designed to assure (with theexception of the criminal context) the rights of individuals todetermine for themselves whether or not to pursue genetic information,and allowing those who choose to do so to derive benefit from the newgenomic tools free from fear of the negative uses of such information.Nevertheless, as described in the Background section, there hasheretofore been no viable means by which to assure the privacy of theinformation without simultaneously reducing its broad accessibilityand/or utility; and no means by which to maximize its use anddissemination, without simultaneously increasing such privacy concerns.One of the primary objectives of the instant system, method, andapparatus is to enable faster, more effective, and broader attainment ofthe positive aspects; and simultaneously to minimize the risk of thenegative ones.

Turning to FIG. 1(B), in a preferred embodiment of the invention, twoadditional processing steps are introduced as part of the aforementionedintermediate processing phase. Rectangular box 113, entitled “AssignMetadata & Index”, refers to identifying and associating variousstructures (i.e., segments) within the individual's genome, andassociating these with metadata as more particularly described inconnection with FIGS. 2, 3 and 4 hereof. And rectangular box 114,entitled “Compress & Encrypt”, refers to optionally compressing andencrypting each such segment, so that in a preferred embodiment, thesesegments may be separately located and access to such data containedtherein controlled in accordance with the principles of the inventionand Applicant's related prior inventions.

As persons of ordinary skill in the art are aware, a number of wellknown means exist for identifying the beginning and end points ofparticular genomic structures; and once so identified, creating orderiving metadata associating therewith, compressing, and encryptingsuch data segments and/or metadata. Such steps may be undertaken throughthe use of specially programmed software (or updates made to existingsoftware) run on servers 106(a); and in a preferred embodiment, would beperformed through the use of hardware such as a specially programmedintegrated circuit chip 106(b), wherein masks such as those describedwithin the '248 application or their equivalent are utilized inaccordance with the principles of this invention.

In various embodiments, as seen with respect to FIG. 1(B), saidprocessing chip may be part of a circuit board, such as part of anexpansion card, for instance, a peripheral component interconnect (PCI)card, including a PCIe card, which in various embodiments may beassociated, such as, communicably coupled, e.g., electrically connected,with an automated sequencer device so as to function part and parcelwith the sequencer, such as where the data files, e.g., FASTQ files,generated by the sequencer are transferred directly over to the chip,such as for secondary genomic processing, such as immediately subsequentto the FASTQ file generation and/or primary processing, e.g.,immediately after the sequencing function has been performed.

In an optional embodiment, such processes could also be performed afterwriting VCF file 112, although in a preferred embodiment these stepswould be performed coincident with the processing involved in theaforementioned mapping, sorting, and variant calling steps. Thispreference is indicated by the substitution of arrow 115 in FIG. 1(B)for arrow 111 under the prior art, representing such processing pipelinein whatever order, whether sequential as shown or iterative in itsnature, best suits the objectives of the invention, culminating inwriting said data to VCF file 112, which in one preferred embodimentwould also be associated with appropriate metadata, indexed, compressed,and encrypted.

The addition of private access symbol 116(a) in association with saiddocument is intended as a means for distinguishing a traditional VCFfile 112 such as shown in FIG. 1(A) from one that incorporates, asdescribed in relation to FIG. 1(B), the foregoing at least two or moresegmented and preferably separately encrypted elements. Additionally, inanother one preferred embodiment of practicing the invention, during thecourse of such intermediate processing, data contained on the foregoingFASTQ file 104 would simultaneously be segmented, associated with theappropriate metadata, indexed, compressed and preferably separatelyencrypted in a number of logically organized packets of data preferablycorresponding to said at least two or more separately encrypted elementsin said VCF file 112. The addition of private access symbol 116(b) inassociation with said document indicates such enhancements.

Finally, FIG. 1(C) illustrates how in a preferred embodiment, theseadditional features are integrated with Applicant's previous teachings,and some of the functional utility of such integration over the priorart. As shown thereon, arrow 117 indicates incorporating data elements(or references to said data elements) produced during the foregoingprocess of associating the appropriate metadata with privacy directivesassociated therewith and indexing said information. In this regard,Applicant's '544 patent teaches the use of unique data elementidentifiers “such as GUIDs (globally unique identifiers), DOIs (digitalobject identifiers), ‘Handles’ and the like to represent this data” andassociate it with one or more privacy directives provided through aprivate access bureau 118, while leaving, in a preferred embodiment,such data at the location and under the immediate control of the dataholder such as the laboratory where the sequencing is performed, aprovider receiving the results of such testing protocol, a researcher,and any number of other parties and applications who hold the data. Insaid '544 patent, the contents of which are incorporated herein by thisreference, Applicant teaches:

-   -   . . . a system and method for regulating the flow of data        including private information over a network, and more        particularly for establishing and operating a privacy decision        point, authorization manager, bureau or the like (collectively        referred to herein as a “private access bureau”) in        communication with user preference repositories and policy        repositories for controlling access to private information over        one or more networks, including the Internet.    -   While a private access bureau may be established for a single        enterprise, geographic area, network, or market segment, in one        illustrative embodiment, the private access bureau is        established as a consumer-centric, cross-industry facility such        that its user preference repositories and policy repositories        are utilized by multiple entities, enterprises, websites, online        services, networks, and other data holders, data seekers and        data subjects. Also, in another illustrative embodiment, the        private access bureau (or a few such competing bureaus as is the        case for consumer credit ratings bureaus) is independent and        privacy policy-agnostic (meaning that it takes no position on        whether data that its systems and services help to regulate        should be shared widely or maintained as being strictly        confidential) so that consumers and data holders have less        reason to doubt that the actions of the private access bureau        [will be] tainted by an agenda beyond fulfilling its intended        purpose of regulating the flow of such data in accordance with        then applicable policies and personal privacy preferences. Any        systems that confer and to the extent applicable, base their        actions to control access to or sharing of data they are holding        based on privacy directives received from the private access        bureau are collectively referred to herein as being        “privacy-enabled,” and the applications and services employed by        them as being “privacy-assured”.

Thus, by employing the teachings of the instant invention, any partiesholding, accessing, and using genomic information can becomeprivacy-enabled, as more particularly described within said '544 patent.By way of summary and not limitation of such detailed disclosure, cloud118 shown in FIG. 1(C), preferably includes the ability for disclosuresof such genomic information (and in one preferred embodiment, specificsegments thereof and/or in another one preferred embodiment wherein saidinformation disclosures are processed in said cloud 118 usinghomomorphic encryption techniques to ensure that the processor is unableitself to know the nature of the content data about which it calculatessuch permissions directives) to take into account jurisdictional rulessuch as federal and state law (in the US and other countries, includingtreaties between nations, to the extent applicable); institutionalpolicy (including how conservatively or aggressively the data holderwishes to interpret issues such as de-identification, the risk forre-identification, and the imposition of financial charges applicable togain access to and/or release of such information); and the wishes ofthe individual about whom such information pertains (including throughprior authorization and/or dynamic consent, i.e., at the time access tosuch information is requested by a data seeker). Additionally, suchprivate access bureau functionality can, in one illustrative embodiment,address in a federated manner the needs for identity verification (e.g.,with respect to the data holder, data seeker, the party (or parties)whose information is being sought, and the data element in question);electronic commerce (thereby enabling transactional charges to beassessed and revenues from such transactions to be distributed inaccordance with terms established by the parties involved therein orconsenting thereto); and for maintaining an independent audit trail ofthe foregoing activities and in one preferred embodiment a record ofdata provenance.

As more fully described in said '544 patent, the private access bureauenables integration of participant 119, who it will be understoodrepresents the individual who is the subject of said genomic data,non-limiting examples of which include a patient, a healthy volunteer ina research study, or anyone who elects to have their genome sequenced.Although not pictured, in certain optional cases, a participant may alsobe a blood relative of said individual to the extent that the thenapplicable law or public policy, institutional policy, or an individualgrantor's wishes result in needing such party's express approval forcertain types of disclosures, or in the event an individual wishes todesignate a person to act as a proxy on his or her behalf. In apreferred embodiment of the bureau, the participant may also be anindividual designated by the institution or jurisdiction to act on thatentity's behalf in expressing the laws or policies of said enterprise orjurisdiction within the rules database employed by the bureau, and/orover-riding such rules should an exception be dictated or in instanceswhere an instruction to “Ask Grantor” reflects that such law or policyto “allow” or “deny” access or sharing is to be based solely on acase-by-case determination being made.

Two-way arrow 120 illustrates the bureau's ability for such participant119 to enter his or her personal privacy preferences (and in the otherinstances referred to herein, in accordance with their respectiveauthority to do so, to enter rules reflecting such jurisdictional lawsand/or institutional policies). Said two-way arrow also reflects saidparticipant's ability to revise or update these entries fromtime-to-time, and to receive notifications where appropriate, andrespond thereto with specific consent. In a preferred embodiment, suchentry would be expressed using a standards-based ontology andcommunication means that reflects the semantic elements taught in the'544 patent, and further described in connection with FIG. 5 hereof. Anillustrative example of such communication supporting dynamic consent isprovided in message 121, which may employ any standards-compliant webbrowser, phone, or mobile device to convey information regarding aproposed action and such otherwise protected data, and as shown, toprovide various options that a properly authenticated recipient of suchnotification may take with respect thereto.

Arrow 122 illustrates communication to said data holder of advisoryinformation regarding the applicable law, institutional policies, theaffected participant's wishes, and prospective remuneration (if any) forgranting access to the protected data (or in some cases, mere metadata)to which such privacy directives pertain. In a preferred embodiment, theprivate access bureau 118 serves as a policy mediation point (PMP) andthe data holder continues to function as a policy enforcement point(PEP). Nevertheless, persons of ordinary skill in the art willappreciate that having ready access to the then current instantiation ofsuch potentially changing information upon which to base suchenforcement decision enhances data liquidity, as reflected byrectangular box 123, entitled “Permission-based, fast, easy access”(e.g., when and as permissible). Persons of ordinary skill in the artwill also appreciate that where, in one preferred embodiment, theinformation that is uploaded to the private access bureau 118 is firstencrypted by the data holder using a technique such as homographicencryption, that said guidance by said private access bureau may beprocessed and returned in communication 122 in an encrypted form that isdecrypted upon receipt by said data holder, and thereby permitting theprivate access bureau to process its decisions that take into accountall of the information described with respect to FIG. 5 hereof withoutever knowing any thing about the content of such attributes except thatthe data holder processed a request and received an answer to allow ordeny [some action], or alternatively that triggering a pre-programmedask grantor process. Persons of ordinary skill in the art willappreciate that by use of such specialized encryption approach, the needfor the private access bureau to be a “business associate” or equivalentof the data holder may be avoided and a number of attendant advantages.

Persons of ordinary skill in the art also will recognize that variousstandards such as XACML (eXtensible Access Control Markup Language),XSPA (OASIS Cross-Enterprise Security and Privacy Authorization), SAML(Security Assertion Markup Language), WS-Trust and WS-Security, OAuth2.0, and Open ID Connect; and evolving standards such as HL7's FHIR(Fast Healthcare Interoperability Resources) and the KantaraInitiative's UMA (User-Managed Access) profile based on OAuth 2, may beuseful in carrying out various portions of the foregoing principles ofthe invention. In a preferred embodiment, said private accesscloud-based service 118, also includes ecommerce capabilities forenabling charges to be established (for example, on a subscriptionand/or transactional basis) for such access, as illustrated byrectangular box 124, entitled “Tolling and charges facility”.

As shown, arrow 125(a) illustrates the capture and reporting of dataregarding said data holder's decision to allow access to or share saidprotected information, and arrow 125(b) illustrates the capture andreporting of any charges and payments associated therewith. Suchinformation is captured in said private access bureau 118, and in turnis communicated (or made accessible) to the appropriate participantsthrough audit report 126, reflecting such activity and fulfilling, amongother things, the regulatory obligations for maintaining an “accountingof disclosures” of data sharing and a record of the authority andpermissions that form the basis for compliance with the underlying laws,policies and participant wishes (or where there is a deviation, i.e.,should a data holder elect to “break the glass” and override such policymediation advisory and act in a different manner, and the basis for suchaction). This is illustrated by rectangular box 127, entitled “Built-incompliance records”. Persons of ordinary skill in the art will be awarethat the U.S. Department of Health and Human Services and the U.S. Foodand Drug Administration (FDA) recently issued standards concerning theuse and processing of electronic informed consent (seehttp://www.hhs.gov/ohrp/policy/faq/informed-consent/can-electronic-signature-be-used-to-document-consent.htmlandhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM436811.pdfrespectively). In one preferred embodiment, said private access bureauactivities will additionally incorporate the step of securing theparticipant's informed consent to one or more proposed medicalprocedure(s) and/or research protocol(s) as an integral step in theforegoing participant engagement activities, said additional processingbeing in accordance with said HHS and/or FDA standards from time to time(or the local law equivalent thereof, when in a country other than theUnited States, or where governed by a different regulatory agency).

Turning next to FIG. 2, which is comprised of five subparts, anillustrative embodiment is presented for the process of segmenting theindividual's genomic information, and establishing individuallycontrolled access to selected portions of said segmented genomicinformation in accordance with the principles of the invention.

The first such subpart, FIG. 2(A), provides a graphical illustration ofa typical chromosome, 201, and the International System for CytogeneticNomenclature (ISCN) mapping system that is used to consistently numberand illustrate chromosomes in the form of an ideogram, 202. As shown,each chromosome is comprised of a very tightly wound strand of coiledDNA 203. Unwinding the coiled DNA strand reveals its form as a doublehelix, 204, comprised of four chemical bases, 205, Adenine (A), Cytosine(C), Thymine (T), and Guanine (G), arranged in a sequence of base pairs(A with T, C with G), 206.

FIG. 2(A) also shows the component parts of an ISCN ideogram for atypical chromosome. As illustrated therein, these consist of the socalled short (p) and long (q) arms, 207, each of which are comprised ofseveral numbered regions, 208. In turn, these regions are comprised ofone or more bands, 209, and in some cases two or more sub-bands, 210,all of which refer in the current state of the art to a particularposition within the chromosome, and therefore a particular segment ofthe DNA strand, 203, and corresponding section of base pairs, 206,located within that chromosome.

It is well understood that in humans, in the absence of a chromosomalabnormality or variation, the genome most often consists of 23 pairs ofchromosomes, found in the nucleus of cells, as well as a smallchromosome found in the cells' mitochondria. These chromosomes, takenall together, contain approximately 3.1 billion bases of DNA sequence.FIG. 2(B) shows an illustration of the ideograms for all 23 chromosomesplus mitochondrial DNA, 211; and indicates that in a preferredembodiment of the invention, there is provided a means for enablingwhole genome accessibility, 212, which it will be understood refers to asingle permission enabling the entire set of genetic instructions to berevealed or concealed. Thus, allowing access at the whole genome levelwould open all of this information for the individual's genome to theparty, entity or application desiring such access (in each such instanceherein a “data seeker”); and prohibiting access at this level wouldpreclude access to any of this content by said data seeker. As disclosedin Applicant's '544 patent, a third option (therein referred to as “AskGrantor”) may also be applied to condition access to said whole genomeupon a response by the participant (i.e., commonly referring to theindividual to whom the genomic data pertains, although depending on theparticular context, someone else such as a parent or legalrepresentative could act on their behalf as the pertinent grantor) to aspecific request for access to such information.

In one preferred embodiment, the beginning and end of that portion ofthe individual's genomic sequence contained on each of such chromosomes211, is identified as an independent level of access control. Asillustrated in FIG. 2(B), such identification of the individualchromosomes results in the prospect for selecting one or morechromosomes, such as by clicking on the ideogram for such chromosome ofinterest to produce rectangular box 213, indicating in such example theselection of Chromosome 3, or by designating the one or more desiredchromosomes by entering said chromosome number in field 214. In eitherthe case, such segmentation of the whole genome into chromosome-levelelements would enable these segments of an individual genome to becontrolled independently from the whole genome.

In a preferred embodiment of the invention, three fundamental systeminstructions or rules are employed. These are indicated in the tablebelow:

-   -   (1) The more specific (i.e., the more granular) instruction        should take precedence over the less specific;    -   (2) The more recent instruction should take precedence over the        less recent; and    -   (3) In the absence of a specific permission to allow access, the        default condition should be to deny access.

It is recognized that in some circumstances and for some sponsors, otherfoundational instructions could optionally be used. Notwithstanding, ina well-ordered system for carrying out the teachings of the invention,it is deemed preferable that the foregoing system rules be employed ascreating the best basis for assuring privacy and enabling private accesscontrols; and in turn, the best foundation for establishing andmaintaining trust.

Thus, the ability for a data seeker to be permitted access to a singlechromosome could be created by an instruction from a grantor to allowaccess to that one chromosome, 213, which in the absence of any otherinstruction would deny access to the remainder of the genome.Conversely, an instruction could be given to allow access to the wholegenome 211, but deny access to a single chromosome, 213, and therebyapplication of the foregoing system rules would enable access to thedata for the entire genome except for data within that said onechromosome. Persons of ordinary skill in the art will understand thatthrough consistent application of the foregoing teaching, a grantor maybe able to fulfill a wide variety of access control objectives, rangingfrom total concealment to full disclosure of the genomic information;and according to which changes can take place in an orderly manner overtime.

The process of specifically identifying and imposing access controls onselected elements of electronic documents is described in Applicant'sU.S. Pat. No. 8,904,554, which matured from U.S. patent application Ser.No. 13/075,344 (System and method for selectively redacting informationin electronic documents) (the '554 patent). Such teachings are describedwith respect to the control of bioinformatic information such as genomicdata through the use of the illustrative case associated with FIG. 4hereof, which employs “unique data element identifiers” that areassociated with access control settings for such data elements and theprivacy directive ontology described in connection with FIG. 5 hereof.

In the '554 patent, the teachings of which are incorporated herein bythis reference, Applicant discloses:

-   -   “ . . . a computer implemented system and method [ ] for        imposing access controls on selective portions of electronic        documents by defining data attributes as conditions for access        to particular data in a document . . . .    -   “In an illustrative embodiment of the invention an ‘electronic        document’ may comprise all or part of a person's genome or other        atomic or molecular structural information. A person using this        embodiment may designate certain portions of his or her genomic        information as private, other portions as public and certain        portions as being authorized for viewing by designated        individuals or under designated circumstances, for example. Such        selective redaction of a person's genomic information may be        appropriate when the information is associated with personal        attributes or susceptibilities, which could be the basis of        discrimination against the person.    -   “Although genomic information is referred to herein as an        ‘electronic document’ it should be understood that such        information may never be embodied in a hard copy and may        typically be stored in a computer readable medium for        interpreting or displaying by a computer device. Where such        device may interpret or use genomic information or other        electronic documents without requiring a display, the        embodiments of the present invention may perform redaction by        rendering redacted information inaccessible to such devices.”

When used in conjunction with the teachings of the aforementioned '544patent and Applicant's U.S. Pat. No. 8,909,669, which matured from U.S.patent application Ser. No. 13/075,313 (System and method for locatingand retrieving private information on a network), herein referred to asthe '669 patent, such information that is intended to be accessible maybe more readily located and employed by properly authorized parties, andsimultaneously excluded from discovery, access, use or inadvertent (ormalicious) disclosure in other instances.

Applicant's '669 patent, which is incorporated herein by this reference,teaches a “system and method for controlling access to documents usingaccess control parameters to reduce preliminary search engine hit listsprior to searching the preliminary search hit list for subsequent searchterms in a query.” Focusing only on the documents, or portions of suchdocuments or data tables, that the searcher is permitted to access,reduces the use of processing resources, transmission bandwidth, anddata storage requirements, and simultaneously enhances privacyprotections. Given its sheer size and the sensitivity of the informationit contains, this approach can be of particular utility for genomicinformation, where for example, access to an individual's entire genomemay not be required in order to provide useful information for anintended purpose, coincidentally saving extensive processing and storageresources and simultaneously precluding any portion of that individual'sremaining genomic information from being exposed to privacy risks byvirtue of having been removed from the search index prior to the conductof queries by a data seeker who is not authorized to access suchinformation.

In one illustrative example, a researcher investigating the importanceof certain variants occurring on Chromosome 3 in relation to autism maynot require access to any information concerning other portions of anindividual's genome. Thus, by selectively addressing her inquiry just tothis data segment, the data to be processed is reduced by approximately95%, and any privacy risks associated with that remaining data aresimultaneously eliminated. An inquiry for another data seeker, who isfor example interested in investigating certain mechanisms associatedwith cystic fibrosis that are known to be associated with the CTFR geneon Chromosome 7, could pursue his inquiry through access to a similarlysmall percentage of total resources and the corresponding assurance thatprivacy risks are materially less than in the case this required wholegenome access. By virtue of reducing the dimensionality of the datashared, the formidable challenges of anonymization of the genome and therisk for re-identifiability can be materially reduced, particularlywhere specific regions of the genome known to introduce privacy risks(for example, access to Y chromosome data from which deducing a surnameof the individual to whom the genomic sequence pertains has been shownto be possible) but that may be of no moment whatsoever to a dataseeker's particular inquiry are entirely eliminated from being includedin returned results.

FIG. 2(C) illustrates the level of whole chromosome access 215. Asillustrated, rectangular box 216 corresponds to box 213 of FIG. 2(B);and in one preferred embodiment, would be accessible for more detailedsegmentation in the event one or more of said chromosomes 212 wereselected. Thus, in such illustrative case, the arms, regions, bands, andsub-bands comprising the chromosome (i.e., in this example, forChromosome 3) are indicated by ideogram 217.

As the sequencing reads described with reference to FIG. 1(A) areassigned a position, such as relative to the reference genome, andidentifying to which chromosome such read belongs and/or its offset fromthe beginning of that chromosome, the beginning and ending of each suchchromosomal arm, region, band, and sub-band may be ascertained. Suchidentification of the individual arms, regions, bands, and sub-bands onthe selected chromosome(s) results in the prospect for identifying oneor more such segments of the chromosome, such as by clicking on thecorresponding area of the ideogram to produce rectangular box 218(a),and an indication of the identity of such selection (i.e., in thisexample, for region 2, band 4 on the long (q) arm of Chromosome 3) by alink 218(b) thereto, or by designating the one or more desired areas byentering the name(s) in field 219. By practicing the principles of theinvention described previously, such further segmentation of theselected chromosome enables inquiry by a data seeker respecting that oneor more selected chromosome arm, region, band, or sub-band; orconversely permits inquiries of data for the entire chromosome (oroptionally the entire genome) with the exception of data pertaining tosuch designated area(s).

FIG. 2(D) illustrates the level of extending such access controls toband access and control 220. As illustrated, shaded box 221 correspondsto rectangular box 218(a) of FIG. 2(C); and in one preferred embodiment,would be accessible for more detailed segmentation in the event one ormore of such chromosome arms, regions, bands, or sub-bands wereselected. Thus, in such illustrative case, the selected area (i.e., inthis example, band 3q24) is indicated by line 222. As shown, to theextent the line representing the selected area is longer than the widthof box 221, forward and back arrows 223(a) and 223(b) permit moving inthe direction of said arrow and reveal immediately below the locationwhere in a reference genome said genes are located. In the illustrativeexample shown in FIG. 2(D), two genes are identified. The size andlocation of such genes are indicated by line 224(a) and a correspondinglink to the name of such gene 224(b); and line 225(a) and links to thatgene's corresponding name, 22504 and 225(c). Alternatively, reference tosuch genes can be achieved by entering the names of said one or moregenes into field 226.

The beginning and end of each of such genes can be identified as thesequencing reads described with reference to FIG. 1(A) are mapped,aligned, de-duplicated, and variants are identified relative to thereference genome. Such segmentation of one or more individual genes, incombination with the teachings of this invention, enables inquires to bemade exclusively with respect to such one or more gene (i.e., forexample, the DIA1 gene 225(c), which is known to be associated withautism); or conversely to inquire of data for the entire banded region,the entire chromosome, or even the entire genome with the exception ofdata pertaining to such gene(s). As more particularly discussed withregard to FIGS. 3 and 4, it will be apparent that such granular controlswould enable a clinician or researcher interested in autism, as anon-limiting example to inquire into data exclusively with respect tosuch DIA1 gene or with regard to a collection of genes associated withautism that includes such DIA1 gene; or alternatively, to enable anyindividual (and not just someone such as Dr. Watson respecting his ApoEgene) to selectively control access to his or her entire genome exceptfor certain genes.

FIG. 2(E) illustrates both gene level access 227 and the level of basepair access and SNP control 228. As illustrated, shaded box 230corresponds to the span of the selected gene 225(A) of FIG. 2(D); and inone preferred embodiment, would be accessible for more detailedsegmentation in the event one or more of such genes were selected. Thus,in such illustrative case, the selected area (i.e., in this example, theDIA1 gene) is indicated by line 225(a), by the entry of such gene namein field 226, or entry in field 229 of a condition or syndrome name,pathway, or other term representing the involvement of a combination offactors for which such gene in commonly associated.

As shown, to the extent the length of the string of base pairs thatcomprise such gene 231 is longer than the width of box 230, forward andback arrows 232(a) and 232(b) permit moving the base pair string in thedirection of said arrow and reveal the corresponding values in areference genome together with the location of SNPs (Single NucleotidePolymorphisms) or clusters of SNPs in which variants have beenidentified in, for example, the dbSNP database maintained by theNational Center for Biotechnology Information at the National Library ofMedicine.

Persons of ordinary skill in the art will appreciate that access to themolecular variation cataloged within dbSNP, dbGaP, and other databasesincluding those being planned by the National Cancer Institute, aidbasic research such as physical mapping, population genetics, andinvestigations into evolutionary relationships, as well as assistclinicians to quantify the amount of variation at a given site ofinterest. Application of the teachings of this invention will enableresearchers, clinicians and even other individuals who are permitted inaccordance with the privacy directives at the time they seek suchinformation to more rapidly identify matches of individuals who havevariations in common, which would be useful in more rapidly generatingresearch hypotheses, establishing connections with other individuals whoshare common genetic traits, identifying potential members for researchcohorts focusing on a particular variant and, supporting futureprecision medicine therapeutic initiatives.

The dbSNP database contains a range of molecular variation includingSNPs, short deletion and insertion polymorphisms (indels/DIPs),microsatellite markers or short tandem repeats (STRs), multinucleotidepolymorphisms (MNPs), heterozygous sequences, and named variants. In theillustrative example shown in FIG. 2(E), two of the approximately 1050currently identified variants listed in the dbSNP database are shownthat are located within the DIA1 gene. Rectangular boxes 233(a) and234(a), and a link to their corresponding ID references 233(b) and234(b), and respectfully, indicate the locations of such variants.Alternatively, the designation of such variants may occur by enteringthe reference IDs or position in field 235, or entering in field 236 thename of a condition or syndrome name, pathway, or other termrepresenting the involvement of a combination of factors for which suchSNP variants are commonly associated.

As more particularly discussed with regard to FIGS. 3 and 4, it will beapparent to persons of ordinary skill in the art that enabling granularaccess controls in accordance with the teachings of this invention willenable a data seeker who is a clinician or researcher interested in aparticular variation on a selected gene (for example, the DIA1 gene thatis associated with autism), to inquire into data exclusively withrespect to that variant, while simultaneously assuring that suchdisclosures are being made in accordance with the applicable laws,institutional policies and the affected individual's preferences. Basedupon these granular settings, and with the dynamic nature of the systemand method, this could be done without needing (and without receiving)any information whatsoever about the remainder of the gene, the area ofthe chromosome where such gene is located, or any other informationpertaining to the genome of the individual, and various permutations ofsuch inquiry patterns. Alternatively, a data seeker could query acollection of SNPs suspected to have significance with regard to acondition or disorder, such as in the present example autism, withoutaccessing any other information. And in yet another alternative example,such granular access could enable selectively controlling access tocertain areas of potential variation where revealing informationconcerning the participant is not desired or permissible. And in yet oneother preferred embodiment, as previously described, the use ofhomomorphic and/or other competing methods of encryption may enable theprocessing of such access and/or return of results determinationswithout revealing any information (at least in an unencrypted form)concerning the information as part of the functions performed by theprivate access bureau.

In a preferred embodiment such designations of areas of inquiry do notreveal any information about the individual genome to which such accesscontrols pertain (i.e., they are not themselves “a viewer” for suchgenomic information) but rather they are used solely as a means by whichto establish who and under what circumstances access is permitted,prohibited, or conditioned upon certain pre-conditions, and/or to submita targeted inquiry into such portion of the genome. In this case, thecontrols could be employed to initiate an inquiry before any informationis revealed about the individual's genome—for example, to only makeavailable for analysis those segments of genomic information that arerelevant to a specific condition or disorder, or a panel of disordersdesignated by a particular group or organization such as the AmericanSociety of Human Genetics (ASHG), The American College of Obstetriciansand Gynecologists (ACOG), and others.

Such granular access controls will also be of value to data seekers suchas clinicians and/or researchers who “create a ‘standing order’ thatwill automatically prompt an attempt to retrieve certain types ofmaterials and information under pre-specified circumstances” as taughtin Applicant's prior U.S. Pat. No. 7,028,049, entitled “Standing orderdatabase search system and method for internes an intranet application”,which matured from application Ser. No. 09/025,275, filed on Feb. 18,1998 (the '049 patent). In several non-limiting examples, employing suchstanding order inquiries for genomic information could enablepractitioners to identify individuals with particular genomiccharacteristics of relevance to prescribing practices that would triggermeaningful alerts, and/or who might be of interest to a clinical trialfor which active recruitment was at that time underway.

In an optional embodiment, users could be provided an opportunity withina genomic sequencing results viewer such as a Map Viewer or ChromosomeBrowser to establish specific privacy controls for a data segment wherea variant is revealed (for example, by having the option to click on anicon to enable such enhanced feature). In this optional case, eitherprospectively before any results are revealed or upon becoming awarethat a variant is present, the participant could make the decisionwhether to treat access to that segment with a different set of accessrights than other portions of the information. This could, for example,enable someone with concerns about a topical area such as having aheightened risk of pathogenic variants regarding conditions for whichthere are no known treatments to limit return of results, or uponbecoming aware of a genetic variation they deem inappropriate to beingdisclosed to others, to expressly limit such result from beingaccessible to all or particular data seekers. Persons of ordinary skillin the art will readily see the applicability of such flexibility forproviding individuals with the options to avoid being informed ofmatters for which there are no known interventions, and/or enabletriggering of such information at a future point in time wheninterventions (or perhaps clinical trials designed to investigatepotential interventions) do become known and/or germane in the opinionof the affected individual or an oversight body for such sorts ofmatters.

Similarly, in several other non-limiting examples, the individual couldelect to make the region with the variant more accessible to anotherclinician in pursuit of a second opinion, and/or to researchers workingon the particular condition or disorder for which such variant isassociated in hopes of advancing future treatment modalities by the timesuch predisposition might be pertinent to the participant in later life.In another non-limiting example, the participant could indicate awillingness to connect with others having a similar variant. As theforegoing examples illustrate, the functionality would be of benefit toaddressing the concerns and interests of a participant who favorsenabling greater-than-otherwise permissible disclosures, just as much asanother who wishes to selectively restrict such access rights; and tothe broad population of individuals whom research has shown fall betweenthese two extremes.

The table shown below summarizes the foregoing levels of segmentationthat could be provided in one preferred embodiment using data from themost recent build (v142, October 2014) of the dbSNP database. As showntherein, with regard to the DIA1 gene and Chromosome 3 (which haveheretofore been used as an example), a total of slightly over 1,050potential levels of access control are provided at the gene level; andapproximately 8.44 million levels account for all currently referencedvariants, including those with both known and unknown significance. Thefollowing table also indicates that for the entire genome, approximately26,000 potential levels of access control are provided to the genelevel; and approximately 122.8 million if wishing to take into accountall presently referenced variants. Based on the NCBI's Variation Viewer,accessible at http://www.ncbi.nlm.nih.gov/variation, the followingpotential levels of segmentation are available:

Only the Only the Chr. 3 Entire DIA1 gene q24 band Only Genome Wholegenome — — — 1 access Chromosome level — — 1 25 Regions — — 5 89 Bands —1 21 ~300 Sub-bands — — 56 ~580 Genes 1 486 1,900 ~25,000 SNP variants1,050 242,228 8,442,924 122,788,469

The particular needs and interests of the practitioner will dictate theoptimal levels of segmentation for a sponsor to employ in carrying outthe principles of the invention. For example, rather than enablingindividual access and control over all SNPs or SNP clusters with atleast one reported variant in dbSNP, other approaches may reduce theoverall numbers of segments materially and still be highly useful. Suchapproaches could focus only on the SNPs for which there exists reliableevidence of a pathogenic relationship, inclusion in references such asthe ClinVar database maintained by the National Center for BiotechnologyInformation of reports of the relationships among human variations andphenotypes (http://www.ncbi.nlm.nih.gov/clinvar/) and/or (OMIM (OnlineMendelian Inheritance in Man; http://omim/org/) database, or whether thenumber of reported variants exceeds a predetermined percentage thresholdso as to focus on the more prominent variants whether or not apathogenic relationship is yet reported in the literature or such publicdatabases.

Region-based annotations may also be of use pertaining to the annotationof variants based on specific genomic elements other than genes, forexample, conserved genomic regions, predicted transcription factorbinding sites, predicted microRNA target sites, and predicted stable RNAsecondary structures. Persons of ordinary skill in the art recognizethat being able to resolve to such regions is important for whole-genomesequencing data, inasmuch as a large number of variants occur outside ofprotein coding regions, and their functional effects cannot be assessedsimply by gene-based access controls. Possessing the capacity foraffording segmented access controls over such regions is likely to be ofvalue to prioritizing genetic variants from diverse genomes, and couldhelp expedite scientific discoveries from the massive amounts of dataproduced from NGS platforms.

In addition to the specific structures, it is deemed preferable toidentify collections of two or more such areas of the WGS, which aloneor in combination, appear to be associated with a particular disease anddisorder, and to treat such collection as a single segment. Thedesignation of such panels by specific phenotypic characteristics ordiagnosed conditions or disease could help to empower participants,clinicians, researchers and others having a legitimate reason: (i) tohelp facilitate and expedite access to such information of interest;(ii) to assert greater control over and/or more effectively limit accessto such segments; or (iii) both (i.e., by designating greater access byspecific persons or for certain purposes, and little of no access byothers). Such selection should preferably balance the parties'respective goals and self-interests, within the bounds of legality,ethical principles, and permitted access, and should be regularlyupdated to account for the latest information based on research as wellas clinical experience.

Such updates could be made in the software or cloud-based implementationillustrated in 106(a), and in the instance involving an integratedcircuit as shown in 106(b), could preferably employ the attributes of afield programmable gate array (FPGA) wherein the chip can bere-configured to account for such updates. Moreover, in a well-orderedsystem employing the teachings of Applicant's prior '544 patent, suchcollections do not need to be known at the time that the initialsegmentation is implemented, and may be applied at a later date based oncreating collections of elements at the level of the private accessbureau or search facility that take into account the latest genomicanalyses and correlations, thereby extending the prospective utility ofgenomic data collected years earlier.

Turning next to FIG. 3, a block flow diagram is provided to illustratethe workflow through which the foregoing data segmentation, assignmentof related metadata, indexing, encryption, and association with privacydirectives can be achieved.

As illustrated therein, such workflow begins at oval 301, whichrepresents the beginning point within the process of aligning, mapping,de-duplicating, and variant calling that is best suited for theparticular segment. This point may differ depending on the size andnature of the segment involved, the variability present in thesequencing reads, and based on the type of technology being employed toexecute such disclosed processes. Moreover, although illustrated in asequential order, it will be understood that the particular order forcarrying out the process addressed by FIG. 3 may differ based on thesegments that will be included, the type of technology that is employed,and other factors that will contribute to making the conduct of theprocess take place in the manner that is most effective and efficient(i.e., with the least amount of additional time and consuming the leastamount of incremental computing resources, while still producing theindicated enhancement to both accessibility and protection throughpractice of the invention). As indicated by recursive loop 302,regardless of the approach taken, the process illustrated in FIG. 3 willpreferably continue until all of the segments that are deemed desirableto be addressed have been subjected to such workflow steps.

Rectangular box 303, entitled “Define the beginning and ending point ofthe selected segment,” illustrates the step of identifying theparticular portion of the genomic sequence associated with such selectedsegment. Rectangular box 304, entitled “Extract (or derive) and saverelevant metadata for said segment,” involves summarizing, extracting,or calculating with respect to such selected segment various metadatathat provide valuable information concerning the raw data but withoutexposing to the inquirer the actual data to which such metadatapertains. By way of several non-limiting examples, such metadata for theDIA1 gene may consist of a list of any SNPs located within said gene ofthe individual in which there is observed a variant; and the metadatafor chromosome 3 may consist of a list of any genes in which there isobserved a variant. Rectangular box 305, entitled “Extract (or derive)and save relevant meta-metadata for said segment,” involves summarizing,extracting or calculating with respect to such selected segmentmeta-metadata (and in some instances even higher levels of abstraction)as more particularly described in relation to FIG. 4 and FIG. 5.

Thus, by way of foregoing non-limiting examples, where such metadata forthe DIA1 gene reveals any SNP variants identified during variant callingprocess 110, meta-metadata element 305 could merely reveal whether ornot there are present one or more variants on said DIA1 gene as a binaryexpression [Y|N], or could indicate the raw number of said variants thatare present, or the weighted probability of there being a variantpresent based on the level of sampling employed, but in eachillustrative case without providing any information concerning theparticular variant(s). Similarly, where such metadata for Chromosome 3reveals any genetic variants during the variant calling process 110,meta-metadata element 305 could merely reveal as a binary expressionwhether or not there are present one or more genes on said chromosomewhich evidence a variant, or could indicate the number of genes on thechromosome in which a variant is present, or the weighted probability ofthere being a variant, etcetera, but without indicating which of saidgenes.

Thus, in such illustrative instances, practicing the principles of thisinvention would result in a number of advantages. A data seeker who wasa clinician seeking merely to ascertain whether a patient in her carehad a variant on said DIA1 gene could instantly attain this answer byinquiring of said meta-metadata at the level of single gene accesscontrol; and only in the case of an affirmative response need to proceedto the meta-data or more detailed data levels of access, therebyavoiding the risk of incidental findings that are present in the currentstate of art.

A similar step could in the future be conducted when prescribing anydrug for which there is at the time of administration a known role ofgenetics in drug response. This would open the prospect for these sortsof inquiries to be initiated asynchronously to the time the originaltest was conducted, thereby opening the prospect for added value beingderived from a genomic test conducted for a different purpose, such as apart of NIPT or newborn screening, clinical germline exome or genomesequencing that identify whether any of the 56 genes implicated invarious known or expected pathogenic mutations recommended by theAmerican College of Medical Genetics (i.e., the “ACMG-56 variants”) arepresent, a genomic test originally undertaken to diagnose a differentpresumed indication, as a part of a program such as IIlumina'sUnderstanding Your Genome® (UYG) program, or as part of populationsequencing, all of which tests are likely to become much more commonwith the continuing decline in cost of WGS.

In the case of a data seeker who is a researcher conducting anobservational study looking for correlations of variations in DIA1 withparticular phenotypic characteristics, the information could be attainedacross thousands or hundreds of thousands of WGS results without anyrisk to privacy of an individual. Should another researcher seekinformation concerning a particular SNPs located on said DIA1 gene, saidinquiry could be conducted with respect first to the meta-metadata 305to narrow the inquiry to those exhibiting some variant, and then byinquiring of metadata 304 with respect to merely the subset to whichthis inquiry was pertinent. Because the invention enables access in thismanner without the possibility for re-identification, the ability toinquire of all of the genomes in an entire network, population, orsubset thereof, becomes far more feasible than under the current art.

Rectangular box 306, entitled “Derive and assign a GUID for said data,meta- and meta-metadata,” illustrates the step of assigning a globallyunique identifier to said data, metadata and meta-metadata. And box 307,entitled “Associate privacy directives with said data, meta- andmeta-metadata,” teaches associating said assigned GUIDs to the locationwhere the then applicable (i.e., as of the time an inquiry is made ofsaid location) privacy directives pertaining to the individualcircumstance may be ascertained, preferably through a web servicesbureau, thereby enabling the ability to employ the teachings ofApplicant's earlier inventions, wherein privacy preferences areassociated with different levels of access control, such as onlypermitting one or more specifically designated data seekers, or groupsof data seekers such deeper access rights. By virtue of being associatedin this manner in a preferred embodiment of the invention, accessdecisions respecting such granular data, metadata and meta-metadata neednot be static determination, but to the contrary is able to change(and/or be changed) over time should applicable institutional policies,governing jurisdictional law, and/or individual privacy preferencesconcerning the right to access such information change.

As disclosed in Applicant's '544 patent, it is deemed preferable that inaddition to having the option to “Allow” such protected data elements tobe shared, and to “Prohibit” the data from being disclosed, a usefulthird option should also be available (referred to as “Ask Grantor”) inthe event access is requested by a data seeker, or when a data holderotherwise initiates steps to share the protected data with anotherparty.

In this third option, the grantor is able to express a preference to benotified and permitted to “allow” or “deny” such proposed access orsharing on a case-by-case basis. This provides an important function forthe grantor (for example, in the present case, the individual whosegenome sequence is revealed in said protected data, the institutionholding that sequence or metadata associated with the contents of suchsequence, or any other party having a right to assert who may or may notdisclose the information to a data seeker).

Providing this option is important because it enables, in effect, a“Maybe” status that protects the information from disclosure until moreinformation is disclosed to the grantor about the data seeker and/or thenature of their interest, for example pertaining to their proposed use,their agreement to remunerate the data holder for such access, and thelike. In many cases, the basis for making a decision is unknown (andpotentially even unknowable) at the time the bioinformatic informationis produced. Thus, even if privacy directives are created at that time,limiting the options regarding how that data will be used and who willbe permitted access to it merely to “allow” or “deny” (which dependingon context, may be through “Opt-in”/“Opt-out” mechanisms of beingincluded in the network) requires a level of prescience that a number ofprivacy advocates, medical ethicists, and IRBs deem unreasonable orconfiscatory and thereby seek to control by limiting access to just whatcan be foreseen at the time original acquisition is undertaken. In suchinstances, the “Ask Grantor” selection enables deferring a decisionabout data sharing until such time when more information is known aboutthe proposed access, and therefor when a more reasoned decision canindeed be made—one that is much more in accord with Fair InformationPractices and high ethical standards—all the while without revealingones identity to the data seeker (unless this too is deemed to bepermissible at the time).

Thus by employing these principles, should any data seekers wish toidentify a research cohort for a clinical trial or in the future, to beable to readily locate and notify persons of the applicability of a newtreatment protocol designed for individuals with a specific geneticvariation, the information concerning how many of that population, forexample, are located within 25 miles of a particular study site orclinical practice who exhibit such variant could be readily educedwithout ever revealing any raw genomic data, any information respectingother portions of the genome, or having any access to contactinformation for said persons. And at the same time, to the extentpermission to do so was either pre-authorized or granted dynamically bysuch individuals to their contact details, this could facilitate directcontact taking place between the professional and said individual. Thesesame attributes are likely to produce useful information for automateddecision support systems used in rendering care and prescribingmedications.

From an efficiency perspective, the foregoing benefits could be derivedwithout ever needing to survey the entire genome record inasmuch as theonly data required to be surveyed would be (a) those participants whosemetadata or meta-metadata was affirmative respecting the presence ofsuch data; and (b) those whose privacy permissions enabled that dataseeker to access such information. Thus, it will be apparent to one ofordinary skill that a data seeker who additionally was granted privateaccess rights to phenotypic information regarding the affectedindividual and/or to the individual subject's contact information, couldgo much deeper with far more efficiency and far greater protections forall individuals within the system than under the current state of art.Such granular access controls would also enable only those data seekerswith an inquiry having relevance to the individual to access herinformation, and would simultaneously minimize the risk of inadvertentor malicious use of such data by anyone else querying the database.

Given the foregoing protections, the opportunity is then presented toopen at least such metadata into a searchable index, including in apreferred embodiment a public or quasi-public search index. This isillustrated by rectangular box 308, entitled “Submit such data, metadataand/or meta-metadata to a search index”. This would enable moreindividuals to locate the record holder of such information, opening thedoor to more collaborations and greater data sharing, whilesimultaneously improving the privacy of such information.

Rectangular box 309, entitled “Separately encrypt such data, meta- andmeta-metadata elements”, illustrates that in a preferred embodimentencryption is used to enhance security and privacy protections whiledata is in transit and while at rest. Additionally, some systems such asElastic Search permit searching an encrypted index which may also beemployed in one preferred embodiment, such that decryption is onlyenabled for a data seeker to whom such access rights have been expresslygranted, either by prior authorization or by using the “Ask Grantor”service, described previously.

In a preferred embodiment, the whole genome 211 would be encrypted usingan appropriate encryption technique. In one preferred embodiment, dataat rest is encrypted in accordance with standards established by theNational Institute of Standards and Technology (NIST), and using theAdvanced Encryption Standard (AES) for encryption algorithms known tothose persons of ordinary skill in the art of data security. Rectangularbox 310, entitled “Compress such data, meta- and meta-metadataelements,” illustrates that in a well-ordered system, such informationmay be compressed at various points in order to reduce system resources.For example, files such as the original FASTQ, BAM or SAM file with areless likely to be frequently accessed may be segmented and subjected toaccess controls employing the VCF metadata, but compressed, encrypted,and stored in a less accessible storage site such as Amazon WebServices' Glacier storage.

Various strategies are possible with respect to both the data storagelocation and decryption key management, although it is deemed preferablethat data holders retain the data locally or under their control in apublic cloud, as well as the key required to decrypt it. As described inthe '544 patent, it is preferable that the data holder confirm though aweb services call or API to the private access bureau the right (orabsence of such right) to employ said decryption key and thereby makesuch data accessible to a data seeker. And in one preferred embodiment,the data holder would have the right to “break the glass”—meaning toignore the instruction to “Deny” or alternatively to first seekpermission through “Ask Grantor” and to proceed to decrypt and share theinformation with a data seeker even where express permission is not yetconfirmed. In such instance (as is the case in compliant circumstances),the data holder's decision will be recorded in the system's audit logtogether with a timestamp for when such sharing took place, under whoseauthority this transpired, and for what reason; and an opportunity willbe accorded to the grantor to assert that it such decision was improper,and therefore to pursue appropriate restitution.

Diamond shape 311, entitled “Was that the final segment to beprocessed?” assures that the foregoing process steps are undertakenuntil all of the bioinformatic segments that are intended to beidentified have been processed, or alternatively until such processingis terminated for an orderly reason. Hence, when the response thereto is“No,” recursive loop 302 returns to beginning step 301 for the nextsegment, and upon such response being “Yes”, orderly ends the process,as designated by oval 312. Thus, it will be apparent to persons ofordinary skill in the art that with the advancement of knowledge,

Turning now to FIG. 4, a drawing is provided to illustrate therelationship between the data pertaining to an individual segment,metadata pertaining to such data segment; and meta-metadata pertainingto said metadata, the use of encryption protection, and the assignmentof globally unique identifiers for such data and metadata elements.

Circle 401, entitled “Data content of selected segment,” represents foreach segment of the genome the actual data resulting from the dataanalysis pipeline described in relation to FIGS. 1(A) and 1(B), andreflecting the actual results of the sequencing process. Rectangular box402(a) illustrates an assigned UUID (Universally Unique Identifier),GUID, Handle, DOI® (Digital Object Identifier), or the like(collectively or individually referred to herein as a “GUID”) for suchdata content 401. As described with reference to FIG. 2, examples ofsuch selected segment content in one preferred embodiment include thewhole genome; each of the chromosomes comprising such genome; each ofthe arms, regions, bands and sub-bands comprising each such chromosome;each of the genes located in such defined areas; etcetera.

Persons of ordinary skill in the art will recognize that a GUID shown inrectangular box 402(a) is illustrative of a unique identifier for adigital object with a machine and platform independent structure thatallows the object and other metadata about the digital object to beidentified, accessed and protected. There are several systems forgenerating and resolving such persistent identifiers, which can be usedto enable a distributed computer system to store identifiers and resolvethem into the information necessary to locate, access, contact,authenticate, or otherwise make use of the resources to which theypertain. Shaded band 403 indicates that the data to which such GUID402(a) pertains is optionally compressed (if compression is merited bythe size of the data) and encrypted, and thereby protected fromdisclosure except in accordance with the then current instantiation ofone or more relevant privacy directives that are located in the PPMS forsaid uniquely identified data content.

The lightly colored band 404 entitled “Its metadata” refers to themetadata that is derived or assigned and that is associated with datacontent 401. While such metadata may contain any number of usefulattributes, in one preferred embodiment it minimally contains theidentity of the data content about which it pertains (i.e., the segmentof the genome to which that data content 401 pertains); the GUID forthat data content; and any variants that are known to exist in saidcontent relative to a reference genome. Such metadata may also nest oneor more other GUIDs associated with such things as health profile datafor the individual to whom such data pertains, and the name and contactdetails for the individual, which data may or may not be accessible tothe data seeker. Rectangular box 405(a) is illustrative of the GUID forsuch metadata 404; and shaded band 406 illustrates that such metadata isalso optionally compressed, encrypted and subjected to access orprotection based on the then current instantiation of one or morerelevant privacy directives that are located in the PPMS for saiduniquely identified [metadata] content.

Lightly colored band 407 entitled “Its meta-metadata” refers to themetadata that is derived or assigned from metadata content 404. Whilesuch meta-metadata may contain any number of useful attributes, in onepreferred embodiment it minimally contains the identity of the datacontent about which it pertains (i.e., the segment of the genome towhich that metadata content 404 pertains); the GUID for that metadatacontent; and a binary expression [Y|N] to indicate whether any variantsare known to exist in said content relative to a reference genome. Aswith the metadata, such meta-metadata may also nest one or more otherGUIDs associated with other attributes such as the health profile, andgeneral demographic information regarding of the individual and/or whatsorts of gatekeepers are available to obtain more detailed levels ofaccess if desired, which data may or may not be accessible to the dataseeker. Rectangular box 408(a) is illustrative of the GUID for suchmeta-metadata 407; and shaded band 409 illustrates that suchmeta-metadata is also optionally compressed, encrypted and subjected toaccess or being precluded from access based on the then currentinstantiation of one or more relevant privacy directives that arelocated in the PPMS for said uniquely identified [meta-metadata]content.

Dotted rectangles 410, 411 and 412 indicate types of access that may beemployed based on the foregoing approach. Depending on the nature of theinquiry and the rights accessible to the data seeker, the dataassociated with the GUIDs shown therein may pertain to one individual,or to anyone in the database. Rectangle 410, which containsmeta-metadata for one or more data elements including 408(a) and similarmeta-metadata for 408(b)-408(n), illustrates that without gaining accessto actual variant data—much less to actual genomic data—a data seekerwith minimal access rights may inquire of, and meaningfully analyze, themeta-metadata to ascertain (for example) the incidence level of whethervariants are present in a particular segment of the genome among apopulation containing “N” records and, depending on the type ofmeta-metadata associated therewith for health related issues, may beable to estimate whether there appear to be any health issues that arecommon to the mere fact that some variant being present.

As described previously, this has a number of benefits, for bothavoiding wasted resources, ensuring privacy, and identifying the subsetof the data for which more revealing access rights may be desired.Dotted rectangle 411, which contains metadata for one or more dataelements including 405(a) and similar meta-data for 405(b)-405(n),illustrates that although certain specifics concerning the variants thatare present within different segments of genomic data may be accessiblefor, among other things, analytical and matchmaking purposes, such usescan still be achieved without revealing actual genomic data or identity.Even for a data seeker with full access rights, such abstractions may bebeneficial to reducing incidental findings, triggering automateddecision support system algorithms, and further narrowing the data thata data seeker requiring individual person level data must receive tojust those individuals who are pertinent to the nature of that dataseeker's inquiry. Particularly when used in combination with the “AskGrantor” functionality enabling dynamic consent, as disclosed inApplicant's '344 and '544 patents, this enables individuals who are waryof excessive disclosure of their genomic information absentunderstanding the particular nature of the proposed disclosure orcontact to be assured that the data seeker is focused on somethingspecific to their genomic characteristics, and therefor much more likelyto finding personal value for themselves or their children.

Dotted rectangle 412, which contains actual data content for specificsegments of the genome including 402(a) and similar content level accessfor 402(b)-402(n), provides the benefits that have already beendescribed for data segmentation. Thus, in one non-limiting example, aresearcher interested in conducting detailed research on the DIA1 gene,could request access to just this segment across an entire population(with or without access to health related data), and without havingaccess to any of the other genome information or the identity of anyindividual. Persons of ordinary skill in the art will appreciate that anumber of useful combinations and permutations of the features andfunctions of the disclosed system and method are available to advancethe simultaneous goals of maximizing accessibility to meaningfulinformation with maximizing privacy.

As knowledge is advanced, the architecture lends itself to exploringvariants and combinations of variants associated with particular healthissues or predisposition to issues. As the cost of sequencing declines,it becomes increasingly possible to sequence large databases ofcollections such as dried bloodspot samples from the nation's newbornscreening over several decades, and to provide individuals to whom suchsamples pertain to control the accessibility of results and to supplyhealth profile information that can jumpstart the personalized medicineinitiative. Similarly, using the high processing speed that is possiblewith the integrated circuit chip 106(b), it may be feasible tore-analyze large numbers of existing exome and genome sequences, andapplying the principles of this invention to make this already assembleddata useful to advancing the precision medicine initiative, andestablish a baseline against which future sequence information can beanalyzed. Given the privacy protective nature of the approach, this maybe able to be pursued with IRB and ethics board approval using existingconsent language that promises information will remain anonymous whereasit is known that whole genome sequencing in the absence of suchprotections cannot. Further, the use of the systems and methods describeenable any individual to whom such information pertains a path toreclaim and assert dynamic consent rights to limit or further extendsuch accessibility.

As greater insights are attained, this knowledge can be used to targetthe combinations of genomic segments that are subjected to inquiry—forexample various panels focusing on the objective of specific diagnosticpurposes (e.g., diagnosing a disease or potential predispositionthereto; clinical interpretation (e.g., looking for markers thatrepresent a disease variant); or isolating whether an individual shouldbe included or excluded as a prospect for various clinical trials orspecific treatment approaches, and other such purposes). Andcorrespondingly, such knowledge may be used to mask from accessibilitythe segments associated with a particular disease state, potential orgenetic malformation to protect the privacy of the individual or toavoid disclosing information that is not desired at that time.

Persons of ordinary skill in the art will understand the importance indeveloping such metadata and meta-metadata expressions, that partiespracticing the invention employ, where possible, applicable standardsfor genomic data, including with respect to platform information,controlled vocabulary, normalization algorithms, data quality standards,and metadata standards. A number of important initiatives are underwayto develop and promote such standards, including the Genomic StandardsConsortium, http.gensc.org/; the Global Alliance for Genomics and Health(GA4GH), http://genocimsandhealth.org/; and the NIH Big Data toKnowledge focus on community-based data and metadata standards,http://bd2k.nih.gov/about_bd2k.html#areas.

Turning next to FIG. 5(A), an illustrative ontological schema ispresented for use in expressing privacy directives associated with suchsegmented bioinformatic data and the various levels of metadatadescribed herein. Such schema amplifies on Applicant's prior '985application, which teaches the following illustrative ontologicalexpression for communicating privacy preferences (such terms beingdefined therein and incorporated herein by this reference):

-   -   <Grantor> by <authority> sets <designated action> affecting        <record holder> holding <protected data> for <record seeker>        when <pre-condition> is met

FIG. 5(A) amplifies on such terms, as previously defined by Applicant,and extends certain aspects of said ontology to address genomicinformation and/or specifically identified segments thereof, as taughtwith respect to FIGS. 2, 3 and 4 hereof. The subparts of shadedrectangle 501, which is entitled “Grantor”, illustrate the categories ofgrantors in a preferred embodiment. As shown, these include jurisdiction502, including any level from local to international body whose laws orstatutes govern data sharing and/or access; institution 503, whichincludes any entity whose policies address such matters; individual 504,which includes individuals capable of establishing preferences for datasharing and/or access by virtue of being the subject of the data 504(a),themselves being the resource holder 50404, or a representative 504(c)for said subject of the data or individual resource holder; and system505, whose rules affect data sharing practices.

Shaded box 506, which is entitled “Authority,” illustrates the legalright or power invoked by the grantor in asserting a privacy-relateddirective, and may assist in determining the priority of said directiveshould there be multiple conflicting directives to consider. As shown,these include laws and statutory provisions 507 with respect tojurisdictions; policies 508 with regard to institutions; preferences 509with respect to individuals; and processing rules (although notillustrated) for the system. Shaded box 510, entitled “Permission,”illustrates the delegated action that a privacy directive (i.e., a law,policy, preference or rule) applies to the protected data or dataelement. As described throughout this application and in Applicant'sprior disclosures, three such actions are provided in a preferredembodiment of the invention. The first of these “Allows” the data to beshared 511, and depending on context, may be used interchangeably with“Permit” and “Accept.” The second of these “Prohibits” the data frombeing shared 512, and depending on context is interchangeable with“Prevent,” “Decline” and “Deny”. And the third is to “Ask Grantor” 513,in which event it is requested that the record holder ask the grantor,which depending on context may also appear as “Ask Me,” “Unclear” or“Snooze.”

Shaded box 514, which is entitled “Resource holder”, corresponds to therecord holder; and as the name implies is the holder of the protecteddata to which the directive applies. As illustrated, the ontologydefines resource holders as individuals 515; organizations 516; groupsof individuals and/or organizations; roles fulfilled by such individuals515(a), line of business or SIC code in which such organizations perform516(a); affiliations within which such individuals and/or organizationsare identified 515(b) and 516(b), respectively; and/or any combinationsof these elements. Shaded box 517, which is entitled “Resource seeker”,relates to the record seeker identified in Applicant's '985 application,and as the name implies is the individual or organization requesting thedata (or to which the data holder proposes to share it). As shown, theontology uses the same constrained elements to define data seekers asfor data holders.

Shaded box 518, which is entitled “Data” refers to the protected data(at whatever level of granularity is specified) held by the data holder514 and sought by the data seeker 517. In a preferred embodiment, saidprotected data includes three elements, respectively focusing on thecontent 519 of the protected data; metadata 520 that describe it; andits provenance (i.e., the data's origin) 521.

The most direct means for identifying the data 518 to be addressed by aprivacy directive is based on its actual content 519, which in oneembodiment can be resolved based on the applicable schema for thedocument or data super-type 520 (e.g., XML, Text, PDF, Image, BAM, SAM,VCF, etc.) in which data 518 occurs. In FIG. 5(A), we illustrate howthis is accomplished based on several widely used document and datasuper-types employed for bioinformatic data, including XML/JSON 521,Text 522, and Genomic 523. XML (Extensible Markup Language) is the W3Cstandard defining a set of rules for encoding documents in a format thatis both human-readable and machine-readable, and may be either stated inX-path (XML Path Language), or the literal element name. JSON(JavaScript Object Notation) is a similar syntax for storing andexchanging data that is considered by many to be an easier-to-usealternative to XML; and that like XML, uses text that is bothhuman-readable and can be read and used as a data format by anyprogramming language, and may be either stated as an Object, or theliteral element name. Accordingly use of XML/JSON 521, correspondinglyresolve to X-Path/Object 524, depending on the syntax, or in either casethe literal content 525. These schemas are illustrative only and do notpreclude use of others.

Another approach to identifying such data content 519 is based on text522, which as illustrated in FIG. 5(A) includes ascribing such contentby its literal content 525, its use as a variable 526, or by thelocation 527 where such text is situated.

The third non-limiting example of a useful schema is based on genomicdata super-type 523, which can preferably resolve unambiguously to thegranular segments of bioinformatic data of a genome. Variousnon-limiting illustrative examples of such segmentation that may beuseful in practicing the principles of the disclosed system, method andapparatus are described with regard to FIG. 2, such segments preferablybeing articulated through one of the more commonly-employed semanticsystems for expressing and annotating genomic data.

Illustrative examples of how information from such semantic systems areemployed within one optional embodiment include describing the databased on that structure's location 527, its literal name 525, or a panel528 within which such genomic data segment is contained. Such “panels”may include, for example, collections of granular segments ofbioinformatic data such as: {variants} of {known significance} to{condition} {name}; {arrangements} of {suspected relevance} to{phenotype} {characteristic}; {combinations} of {possible relevance} to{the effectiveness} of {drug compound}; and the like. In a preferredembodiment, such panels may be useful in establishing variousmeta-metadata expressions as more particularly described with regard toFIG. 4 hereof.

In one optional embodiment, said panels are defined through reference toa “current panel descriptor” that can be updated as informationconcerning the relevance of various genomic elements is ascertained overtime with regard to the topic of said panel. In such optionalembodiment, searching for a panel would refer first to the mostup-to-date enumeration of the elements that should be included therein,and then these elements—identified, for example, by their literal name525 or location 527—would be returned to said panel-based query. It willbe apparent to those of ordinary skill in the art that the advantage ofemploying this approach is that the panel definition at the time thegenome was sequenced may not be nearly as maturely articulated as adecade later when the same inquiry was conducted, and yet if the newerpanel descriptor were to be applied to inquire of such panel, then theindividual elements that comprise such query results would be in accordwith the latest scientific knowledge rather than being out-of-date werethe panel to be a static object.

Another illustrative approach that may be useful in identifying data 518to be addressed in a privacy directive is based on various meta fieldsand/or identifiers 529 that may be included in a meta data index. Suchmeta fields 529 describe the data using a “label-like” approach, e.g.the label on the outside of a sealed envelope; whereas the contentsapproach 519 is based on the data content that is enclosed therein. Thisapproach is particularly useful for private information because, in awell-ordered system, it permits data 518 to be subjected to privacydirectives without disclosing the data content 519 to anyone other thanan intended recipient. As shown, various illustrative forms of meta datafields include data type 530, document type 531, and unique ID 532.

Persons of ordinary skill in the art of healthcare information systemswill recognize that a number of standards and specifications exist forsuch elements, some of the more widely embraced being by HL7, ISO andCDISC, for defining the kind of data that can be included in a fieldand/or representing its abstract semantics using standard controlledlanguage in human-readable and/or machine readable form. The topic ofglobally unique IDs has already been described and is also widely knowto those of ordinary skill in the art without undue experimentation, asis the process of expressing the content of such standards based metadata as an unique ID that is accessible given proper access privileges.

The subject of such data may also be represented by a unique ID 533, andin one optional embodiment such ID may be associated with other IDs forsaid individual to support collecting pertinent data and de-duplicatingrecords about the same person held by various resource holders.Classifications 534 are another useful form of meta data, and may referto an element, a class of elements, or aggregation of elements and/orclasses. These include medical classification, or medical coding systems535, which are frequently used to transform descriptions of medicalsymptoms, diagnoses, laboratory results, medications, procedures,topography, treatments, and the like into universal medical codenumbers. These include both country specific standards and internationalclassification systems, and include both statistical and nomenclatureclassifications.

Persons of ordinary skill in the art are aware that such meta data maybe used to describe the type of data, for example “a diagnosis” withoutrevealing the content, and designate that such value is protected inaccordance with a particular privacy directive. Designated segments 536,and other classes 537 are also included to illustrate that such systemsis intended to be both flexible and extensible. Dates 538 may also beused to identify dates of care, medical encounters, natural events, andthe like. Similar to panels, as described previously, suchclassifications may optionally be dynamically directed through a currentpanel descriptor that would enable, for example, all of the dataelements considered to be “Personal Health Identifiers” (or PHI) to beaddressed through a single directive, and enable a grantor to revise itsdefinition of PHI over time and for such revision to be immediatelyapplicable even to data that was acquired well before such changeoccurred.

Another useful aspect of the data 518 that is preferably addressed isthe provenance 539, which is generally understood to be informationabout the entities, activities, and people involved in producing thedata. Such information is useful to form assessments about the quality,reliability, or trustworthiness of the data, and in certain cases how itshould be interpreted and/or analytically handled, as well as itsreproducibility. The W3C has a Provenance Working Group, whoseproceedings and recommendations may be useful in this component part ofthe ontology. For more information, refer tohttp/www.w3.org/TR/prov-overview/.

In one optional embodiment, provenance included the original data source540 and/or a document ID 541 for any data 518 originating from thesystem itself. The original data source 540 may be further resolvedbased on the date such data 518 was created 541, the organization whereit originated 542 and the individual within such organization 543responsible for its creation, as well as the purpose for which it wascreated 544, all of which attributes may among other uses, be ofrelevance in expressing the applicability of certain laws 507, policies508 and/or preferences 509.

In one optional embodiment, such provenance 539 component of theontology may be employed to capture certain information associated withany such data 518 being disclosed to a resource seeker 517. For example,this could include the individual 515, entity 516, or application underdirection of one of such individuals, entities or affiliates thereof,accessing such data 518; the date and time on which this eventtranspired; the location of access; a verification from the computerbeing used for such process of the machine ID, data and time, andgeo-location of the access; the purpose of use indicated by said personfor accessing such data 518; and an affirmation or representation asmay, from time to time be deemed advisable to carrying out the objectsof the invention. Without limitation, these include reporting to theaudit service 611, establishing the basis for the payment servicedistributions 640.

Pre-condition 545 refers to other factors accompanying the directivethat can be used to help determine the correct data sharing or dataprotection decision. By way of various non-limiting examples, suchpre-conditions may include applicable time period 546 (e.g., on date X,during period from X to Y, etc.); the purpose of use or reason foraccess 547 (e.g., provision of care including clinician-orderfulfillment, medical research, clinical trial, referral of care,reporting back to referring clinician, etc.); the type of access 548 tosuch data 518 by said data seeker 517 (i.e., as more particularlydescribed in relation to FIG. 7, which discloses an illustrative userinterface for specifying such accessibility preferences); and OtherCriteria 549. Pre-condition 545 may also include Boolean combinations ofthese sorts of conditions or factors.

By way of further illustration and not limitation, such Other Criteria549 may also include pre-conditions including selections and level ofidentity proofing and/or minimum authentication requirement placed onthe resource seeker 517; state of consciousness or mental faculty of thesubject 533 to whom data 518 applies (e.g., unconscious, incapacitated,unsound mind, etc.); the availability of said subject 533 (or theirdesignated agent) for consultation (e.g., unable to contact by variousmethods for some period of time); a limit on number of accesses (e.g.,one time only, up to three times, etc.); and the like. In addition,pre-conditions may include explicit requirements for securing priorexpress consent; the obligation to de-identify data 518 in accordancewith HIPAA standards, Common Rule standards, or another jurisdictionalstandard; geographic areas for which a directive is applicable (e.g.,facilities located in the state of New York, residents of any EuropeanUnion member country, etc.); specific circumstances surroundinghighly-sensitive conditions (e.g., AIDS, drug/alcohol use, psychiatriccontext, etc.); and other conditions embraced by the applicable law 507,policy 508, or preference 509.

As with all of the foregoing elements comprising the ontology, to theextent there is wide agreement on such terminology, it is preferable touse common standards to resolve and express each of such attributes.Such terminologies are well known to those of ordinary skill in the art;and Applicant's '544 patent indicates a number of illustrative examples.Also, as noted within FIG. 5(A), composites of these various elementsmay be used in accordance with the principles of the invention.

FIGS. 5(B)-5(D) provide several examples of how the ontology describedwith regard to FIG. 5(A) can be employed with respect to an illustrativeuse case. In a non-limiting example, these figures are based on aparticular instance wherein the wishes of an individual about who mayhave access to certain portions of her information may reflect a numberof important nuances. These figures are based on a hypothetical casewherein a subject, whom we refer to as Ann Summers, has a family historythat places her at risk of Huntington's disease, a fatal disease forwhich there is presently no known cure. For the sake of illustration, weassume that she is in her late-20's, single but presently datingsomeone, currently has no symptoms of the condition, and is juststarting out in a promising career.

The Huntington's gene (which is also known as the HTT gene) is uniquefor a number of reasons, which makes it useful for illustrativepurposes. It is a single gene, whose alleles are dominant, meaning thatif either parent has the gene then any offspring has a 50/50 chance ofalso having it. The condition commonly begins to manifest noticeablesymptoms between the ages of 35 and 44 years; and according toreferences cited in Wikipedia, between 33% and 69% of the individualswith the condition experience depression, and 7.3% of those with thedisease take their own lives and up to 27% attempt to do so. Moreover,learning of the diagnosis often results in significant feelings ofguilt, and because there is no known treatment, the treatment benefitsof early diagnosis are questionable. Accordingly, whereas 99% of theindividuals expressing symptoms of the disorder and who have a familyhistory of the disease receive a genetic test to confirm a diagnosis,less than 5% of the pre-symptomatic cases currently undergo genetictesting.

While a number of the foregoing characteristics are quite extreme (andthe level of certainty is quite high), as scientific knowledgeprogresses to where similar levels of confidence can be predicted formulti-gene disorders and that take into account protective regions ofother genes and such subtleties, it is not unreasonable to anticipatethat similar sorts of challenges regarding how to address genomicfindings will evoke similar kinds of concerns and opportunities. Bypracticing the principles of the invention, an individual such as Ann inthe hypothetical case has a number of options that are simply notpossible under the present state of the art, and that are likely to makegenomic testing much more readily acceptable, particularly for largepopulation sequencing where (from an epidemiological sense) somepercentage of cases will inevitably be similar to Ms. Summers' case.

FIG. 5(B) indicates how an individual who does not wish to know whetheror not she tests positive for a risk such as, in this illustrationHuntington's disease, may wish to establish her settings. This could befor any number of reasons, such as concern about what a definitivediagnosis could mean for her career, her social relationships, herability to secure long-term care insurance, and even how her own familywould respond or how she′d deal with it. Heading 550(a) indicates thatthe highlighted portion of the illustration is expressing the use casestated in descriptive paragraph 550(b). As indicated, the grantor 501 isan individual 551 who is the subject of the data, Ann Summers 552. Ms.Summers, whose authority 506 is based on her personal preference 553,wishes to prohibit 554, the data holder 514, who in the illustrativecase is assumed to be a specific organization, IIlumina, Inc. 555, andany of its affiliates 556, from disclosing certain data 518. Theparticular data that is the subject of this directive is any data type557 on any date 558 of which she is the subject 559 and the content ofwhich is a data super type 560 of genomic information 561, whose literalcontent 562 is the HTT gene 563 (which pertains to Huntington's disease)and/or whose location 564 is on the short arm of the Chromosome 4 inregion 1, band 6 and sub-band 3. This could be accomplished through useof controls such as described with respect to FIGS. 2(C)-2(E). Theontology also describes the provenance 539 of the data 518 that thedirective addresses, namely that the original data source 566 isIllumina, Inc. 567; the purpose that the data was created wasparticipation in the Understanding Your Genome program 568 and that theinformation was created on Mar. 8, 2015, reflected in oval 569. Andfinishing the directive, we note that the data seeker 517 to whom thedirective pertains is Ms. Summers herself 570.

In accordance with the principles of the invention, another attribute ofthe invention that could be effectively employed in cases whereinformation about the disorder are not as well defined as in the case ofHuntington's disease is the use of Panel setting 528, that in onepreferred embodiment might be used in lieu of calling out a specificgene or chromosomal region. The advantage of this alternative approachwould be that as scientific knowledge develops, the effect of suchdesignation would apply to the genes and/or chromosomal regions known tobe of relevance at the time of a future inquiry (as opposed to beinglimited to what was known about the genotype to phenotype correlation atthe time the privacy directive was created). This feature of theinvention is described in relation to FIG. 5(D) below.

Turning now to FIG. 5(C), a second privacy directive is expressed usingthe foregoing disclosed ontology to address the anticipated desire by anindividual such as Ms. Summers to help advance medical research into thedisease affecting her family and that will potentially affect her in thehypothetical case, and to hopefully finding a cure to Huntington'sdisease while at the same time balancing this interest against her wishto assure that she is not inadvertently informed of her own statusand/or adversely affected by discrimination related to the condition orher potential to have it. As shown, this goal 550(c) can be achieved bysetting her preferred permission 510 to “Ask Grantor” 571; and the datatype 518 to “metadata” 572. As described previously, this has theadvantage of not revealing the actual genomic sequence, but insteadmerely metadata regarding it. This may be more appropriate given thebreadth of her intended disclosure, which in this case is assumed to beto any data seekers 573 subject to the pre-condition 545 that thepurpose of their research 574 is Huntington's disease 575. Thus, incarrying out the principles of the invention, such a setting wouldpermit Ms. Summers (while remaining anonymous) to learn about eachresearch project and researcher expressing interest in obtaining herdata, and upon that basis to be able to decide whether or not she wishedto grant them such access.

FIG. 5(D) focuses on another seemingly reasonable objective that anindividual such as Ms. Summers is likely to have, namely that she beaware of any actionable information that her WGS result provides. Inthis regard, she is interested not only about potential futureHuntington's breakthroughs, but also about anything else that mightaffect her proper care. She knows that this will become even moreimportant as she thinks about a family of her own someday to ensure thatif she is carries an excessive number of CAG repeats on the HTT genethat she and her spouse can consider fertility options at theappropriate time. In order to address these considerations, she wishesto allow her personal doctor to know about any actionable data, andcounts on him to decide whether or not to inform her, and when he feelsit becomes critical to do so. FIG. 5(D) shows a third privacy directiveemploying the ontology to express goal 550(d). This is accomplished bysetting her preferred permission 510 to “Allow” 576 her physician, Dr.Ben Casey 577 to access all of her data 557 that is, at the time part ofpanel 578 that is considered to be “actionable” 579 for treatmentrelated purposes 580.

Given the extensive amount of research taking place in the genomicsfield, and with the cost of WGS and NGS dropping dramatically, theamount of actionable information is likely to change rapidly. Bypracticing the principles of the invention and using the panels 578setting, an inquiry by her doctor at some future date such as the timingof her periodic physical exams may reveal that something which was notrecognized as being actionable at the time her genome was sequenced hasbecome actionable (or alternatively, something that was actionable butfor someone who was older or facing different conditions such as thepotential of becoming pregnant) might dictate a different decision beingmade from information that was known at the time she was originallysequenced, but that was not pertinent to her under the prior conditions.Her doctor may be assisted in keeping track of such updates throughestablishing a “standing order” inquiry respecting Ms. Summers, asdescribed in Applicant's '049 patent, and her willingness to grant tosuch physician “total access,” as described with respect to setting 706in relation to FIG. 7 hereof.

Turning next to FIG. 6, an updated sequence of services and API calls isillustrated for the purposes of carrying out the teachings of theinvention. FIG. 6 represents an update to Applicant's previousdisclosure of such activities in FIG. 5 of Applicant's '544 patent andthe corresponding description. As explained previously, in one preferredembodiment, the services of the private access bureau are exposed asintegration profiles via stateless, reusable Enterprise Service Bus(ESB) services developed as adapters.

FIG. 6 shows the relationship in one preferred embodiment between aprivacy-enabled enterprise or network 601, comprised of a data seeker602 (whose activities are illustrated therein by rectangular box andvertical line 603 for either a person, a software algorithm orapplication), and who through a browser-based interface, application ormobile app 604, is in contact with one (or perhaps multiple) dataholder(s) 605. Said application 604 may be an integral part of a dataholder's systems, or an independent service such as a search engine orapplication operated by one or more other parties who function as anintermediary for locating information held by said data holder or agroup comprised of multiple data holders (in an non-limiting example,several medical centers, pharmaceutical firms, testing laboratories andvarious registries) 605. As shown, said party (or parties) also includessecurity service(s) 606.

Said enterprise or network 601 is in communication over the Internet orintranet 607(a) with the private access service 608. As shown, theprivate access service includes the privacy preference managementsystem, which is also referred to variously as the PPMS orPrivacyLayer®, 609, a payment service 610, and audit service, 611. Asshown, the private access service preferably employs multiple bindingadapters to accommodate multiple profiles and bindings, i.e., SOAP overHTTPS, REST-full services, XML over HTTPs, and newer technologies thatsupplant these in the future. All API calls are secured using industrystandard patterns such as WS-Trust, SAML and XACML, enforcing messageauthenticity, integrity and confidentiality.

The illustrative API call sequence shows participant 612 setting 613privacy and sharing preferences 614 from any standards-based Web browseror Web-enabled mobile device connected via network 607(b), such as theInternet, to the privacy preference management system (PPMS) component609 of the private access bureau 608. As previously described inconjunction with Applicant's '544 patent, such privacy preferences 613can be for an individual participant such as a patient or their legallydesignated representative or proxy.

Said participant 612 can also be the appropriately authorized partyrepresenting any other “grantor” including, but not limited to anenterprise such as a laboratory or physician practice that generated thedata initially, an institution who is the data holder such as a medicalcenter, research enterprise or insurer; or a jurisdiction such as alocal government, state, federal or international body having some levelof authority with respect to individual persons' health related data.Entries made by such individual participants are retained in a privacypreferences repository database 615(a), corresponding to 1206 of FIG. 4of Applicant's '544 patent, which as shown therein and illustrated hereby two-way arrow 616, is connected to the PPMS.

The PPMS is also connected via two-way arrow 616 to privacy policydatabase 61504, which in turn contains policy directives, preferablystated in the ontology described with respect to FIG. 5 above or othermachine computable form, reflecting institutional policies (includingbut not necessarily limited to pricing policies) 615(c), State orprovincial law 615(d), Federal or national law 615(e), and internationalstandards and treaties 615(f). This architecture is intentionallyextensible in order to enabling the private access bureau to accommodateother laws, rules, regulations, policies, or charges responsive to otherapplicable bodies such as regional, county, city, trade affiliations andthe like; institutions whose earlier services in generating,interpreting or analyzing intermediate products added to the value ofthe data; affinity groups, and other individuals who are entitled tosome rights or share in proceeds, if any.

Audit service 611 is updated 617 for the set preferences event 614. Suchaudit service 611 included within the private access bureau 608 includesan audit database. This service provides the ability, at any time, forthe participant 612 to login to the private access bureau and view 618an audit history of events affecting data for which he or she is thedata subject, or covered by the policies he or she administers. To theextent possible, this preferably includes privacy preference settings,authorizations, requests for access, and access to or sharing of thebioinformatic data segments from any privacy-enabled system orprivacy-assured application. Additionally, such participants 612 canpreferably subscribe to receive alerts based on updates to the auditservice 611 that affect the data and/or records of such data subject.

A data seeker 602 logs in 619 and authenticates as an authorized user ofa privacy-enabled system of the application or mobile app 604 within aprivacy-enabled network 601, including data holder 605. The securityservice 606 employs standard security practices 620 to verify theidentity and authority 621 of the data seeker. This standard practiceis, in a preferred embodiment, assisted through the use of asingle-sign-on (SSO) protocol such as OpenID to authorize such use,whereupon if successful a message is sent to the data seeker indicatingthat login is complete 622.

Data seeker 602 then requests data 623 using the application or service604, and promises to pay for such receipt of information, if applicable.Such payment may take any form, including without limitation atransactional fee, an ongoing subscription fee, or by consenting to aprivacy policy that permits the display of advertising in conjunctionwith such search and/or retrieval functions. Said data request 623 isconveyed as a data request 624 to the actual data holder 605. Beforeresponding to such request for access to said data (or in the case thatthe application is a search engine or its equivalent, before presentingresponding to a request for search results that are responsive to asearch inquiry), the data holder 605 inquires whether such access ispermissible 625. As part of the security service 606 responding to suchinquiry, said service preferably sends a service request to the PPMS 609using an XACML-based message including a SAML assertion (if SOAP basedmessaging is employed) or using RESTful exchange through an OAuth2protocol-based API 626.

Upon receipt by the private access bureau 608 of such inquiry, the PPMS609 runs the privacy directives execution engine 627 generally in themanner described with regard to the operation of the private accessbureau 608 in the '544 patent, the description of which is incorporatedherein as though set forth in full herein. The system captures the datarequest event 628 in audit service 611; and if the inquiry is capable ofbeing answered immediately based on the database contents of the privacypreferences database 615(a) and/or privacy policy database 61504,responds to security service 606 for data holder 605 via an XACMLstatement or OAuth2 response 629(a) with the applicable privacydirective.

Alternatively, if the request is not capable of being answered withoutinput by the data subject (or another grantor, as applicable), then anotice of its processing status having been pended 629(b) iscommunicated to the security service 606 for record holder 605, and arequest for express consent 630 is sent 631 across network 607(b) tosaid participant 612. Audit service 611 is simultaneously updated sothat in the event data holder 605 wishes to check the status 632 of thedecision, this information is available to said data holder 605 acrossnetwork 607(a) from audit service 611. Subsequently, when participant612 consents or declines 633 to permit the action proposed in the mannerdescribed in detail in Applicant's '544 patent (or the time allotted forsuch decision transpires thereby triggering an automated response inaccordance with a rule in contemplation of such passage of time withoutany response), this response (or the automated action taken in theabsence thereof) updates 634 and two-way arrow 616 the privacypreferences repository database 615(a), asynchronously communicates aprivacy directive 629(c) to the security service 606 for data holder 605via an XACML statement or OAuth2 response, as applicable, over network607(a), and updates the audit service 635 reflecting such action.

Irrespective of whether the response is immediate, indicated by arrow629(a), or asynchronous as represented by dashed arrow 629(c), securityservice 606 enforces the action in accordance with said directive or bypermitting the data holder to “break the glass” and thereby ignore saiddirective, each illustrated by arrow 636. On this basis, the request bydata seeker 602 to receive said data is fulfilled 637, either directlyfrom data holder 605 or through application 604, which notifies 638 dataseeker 602 of the availability of the requested data, if applicable, oralternatively notifies the data seeker that the request cannot befulfilled, if access was denied or simply was incapable of beingresolved to the satisfaction of said data holder's policies. Theassociated charges, if any, for such access are in a preferredembodiment processed 639 through the payment service 610, with theproceeds (net of a service charge) 640 queued for distribution by saidpayment service 610.

The requested data is then conveyed 641 to the data seeker, therebyfulfilling 642 its prior request 623. Confirmation of the delivery ofsuch data conveyed to the data holder 643, the security service 644, andrecorded in a capture disposition event 645 update to the audit service611. In accordance with the terms of participation and/or institutionalpolicies of the data holder, the net revenues 640 from the payment madeby the data seeker (if any) are distributed 646(a)-(d) by the paymentservice 610 to the data holder 605, and application or service 604,participant(s) 647, and any third parties 648, for example as a donationon said participant's behalf to a health-related nonprofit favored bythe participant.

FIG. 7, which consists of nine subparts, presents an illustrative userinterface for intuitively establishing preferences in one preferredembodiment regarding the right to analyze, discover, view, use, export,and link bioinformatic data including genomic data with otherde-identified and personally identifiable health information and contactdetails for the individual to whom each of such element(s) pertain.

FIG. 7(A) provides an illustrative drawing of a user interface forexpressing one's preferences respecting the question “Who can accessyour health data and for what purpose” 701. A table of configurationpreferences is shown, the horizontal axis 702 of which addresses thetypes of information, and the vertical axis 703 of which addresses whocan access that information, and the intersection of such columnsrepresents the particular preference expressed for such information.Persons of ordinary skill in the art will understand that each of suchselections represents a preference of use within the ontologyillustrated with reference to FIG. 5 and, among other things, of use inoperating a private access bureau to carry out the principles of thisinvention and the '544 patent.

In one preferred embodiment, such horizontal axis 702 can be widened bysliding handle 704(a) in the direction indicated and reinforced bymessage 704(b), thereby making accessible to the user increasingly moregranular selection options. Similarly, vertical axis 703 can beelongated by sliding handle 705(a) in the direction indicated andreinforced by message 705(b), thereby making accessible to the userincreasingly more granular selection alternatives. In both cases,sliding handles 704(a) and 705(a) in the opposing direction would “foldin” such granular options into broader statements encompassing suchunderlying granularity. Accordingly, as shown in FIG. 7(H), in anoptional embodiment, such slider handles change form to 704(c) and705(c) to reflect that the slider may be moved in either direction; andchange to yet a third form as illustrated by 705(d) in FIG. 7(E) toreflect that the axis has reached its most granular extreme, which isreinforced by the accompanied message 705(e).

FIG. 7(A) shows said table in its most constricted form, what simplypresents such selections in the form of a 1-by-1 table. As shown, thesole column 706 in such table, entitled “Total Access”, in combinationwith the sole row 707, entitled “Everyone”, allows a user to specify aprivacy preference that would apply to the ability for all of his or herinformation to be found, used and exported by “everyone” for anyclinical, research, support and/or other purposes, including marketing.As illustrated, such selection can be made by clicking on arrow 708 toreveal in a preferred embodiment three selection options 709,respectively corresponding to permission options 511, 512 and 513illustrated in FIG. 5(A) hereof.

Based on the foregoing description, it should be readily apparent thatby selecting “Allow” (in turn corresponding to permission option 511)using pull-down list 709, this user is indicating her wish to make allof her information accessible to everyone. And were this selection to bemade, then sliding handles 704(a) or 705(a) in the direction designed toopen the granular selections comprising such broad declaration wouldreveal “Allow” as the setting for all such revealed cells. Employing theprinciples of the invention, changing one such cell to “Ask me” or“Deny” would take precedence for that selection but all of the othercells would remain in their original “Allow” state, as more particularlydescribed with respect to FIG. 7(E), below.

In a preferred embodiment, such selection options are accompanied by alink 710 to suggestions for setting one's privacy preferences made by“guides”, as more particularly discussed in Applicant's previous '544patent. In one preferred embodiment, such message would display thenumber of such guide recommendations 711 that are available to assistthe system user. Such assistance by knowledgeable individuals can beuseful to helping reduce a sense of overwhelm and/or frustration thatmay otherwise occur with granular controls, while simultaneouslyavoiding the system's design being coercive for a particular outcome.Access to such guide suggestions, which may optionally include theopportunity to view video interviews, read quotes and materials, andview (and if acceptable adopt) a template supplied by the guide as abeginning point for the system user, may be very helpful in assuringthat the selection is meaningful and perhaps more comprehensive than ifeach individual must think through each selection without access to suchassistance from trustworthy persons.

Turning next to FIG. 7(B), an illustration is provided to indicate theconsequence of a user selecting the “Deny” option from pull-down list709 of FIG. 7(A). As shown therein, the privacy preference to “Deny” 712indicates the individual's wish to deny access to all of theirinformation to everyone (i.e., to make such information not accessibleby anyone). In this instance, the illustration depicts that in apreferred embodiment, the system would automatically compare suchpreference to the database of jurisdictional laws and institutionalpolicies and identify if a “superior right” under applicable law ispresent that could render such preference unavailing. In suchinstances—and in the case of the illustrative example shown—the actiontaken would cause a symbol 713 to appear on the face of such selection,and by this means inform the user that her selection conflicts withanother setting that takes precedence and could result in her preferencebeing disregarded.

In the case of the illustrative drawing shown in FIG. 7(B), selecting“Deny” for all data (at least for users in the United States) wouldtrigger such a symbol 713 in the event the data holder was a CoveredEntity (as defined in HIPPA). This is because under HIPAA, a CoveredEntity can share certain health data (including personally identifyinghealth data) for “treatment”, “payment” or “operations” purposes withoutthe authorization of the individual (and irrespective of theindividual's express wishes to the contrary). Message 714 preferablyaccompanies and summarizes the meaning of symbol 713, and includes alink 715 for individuals wishing more details.

While not shown in such illustrative drawings, it will be readilyunderstood that such explanation may include a link to the applicablestatutes and/or policies that prompted such alert 713, and may provide ameans (such as “Express your views to your Congressionalrepresentatives”) for interested persons. In this case, it would mostlikely also explain the institution's policies that might be less broadthan the law, for example to honor such wishes except in certain limitedcircumstances. And in a preferred embodiment, such information wouldexplain that should the law subsequently change in such a way that theindividual's preference were to take precedence over the law, then thedata holder would abide by such change in applicable law. Persons ofordinary skill in the art will readily appreciate that the foregoing isillustrative of one of the benefits of the invention, in providingtransparency and placing accountability where it rests, and inautomatically enabling a privacy-assured system to at all times be inaccord with the latest instantiation of applicable laws, institutionalpolicies and/or personal preferences, which will materially reduce thecosts and disruption created to account for such changes under currentstate of the art in access control technology and compliance systems.

FIG. 7(C) shows how, in a well-ordered system, the user interface canintuitively indicate to the use that variability exists within thehidden (i.e., more granular selections). In one preferred embodiment,“Mixed” display 716 appears, and includes an arrow 717 pointing in thedirection of the table in which the granular settings are not all thesame. The first time that such “Mixed” display 716 appears, in apreferred embodiment it would be accompanied by an explanatory message718. This message would preferably appear each time a “Mixed” displayappears unless and until the user places a check in checkbox 719 toindicate that the message need not appear in the future.

FIG. 7(D) shows how the user interface responds when a user clicks onthe “Mixed” cell 716 in FIG. 7(C). As shown, that selection results inthe table opening in the direction of arrow 717 in logical increments toreveal such granularity and the corresponding settings for each, and asreflected by the repositioning of slider handle 705(a). In one optionalembodiment, the first logical expansion in such vertical direction is toreveal the four major groups comprised within the “Everyone”classification 707 (shown in the preceding three sub-parts). In thiscase, the next level of detail selected by a system designer employingthe principles of the invention could reveal, for example, a categoryentitled “[Trusted Referral]” 720, and explained in the accompanyingtext to relate to both the entity or person itself as well as otherswhom it recommends.

It will be apparent to persons of ordinary skill in the art that“Trusted Referral” may, depending on context, pertain to a supportgroup, medical center, charitable organization, or individual (such as aprovider) who suggested the user employ the system and thus in onepreferred system listing this referral and their recommendations firsthelps to ensure that the focus of the user's activity is principallywhatever brought them to be using the system. Other categories of userscomprising “Everybody” are “Clinicians” 721, referring to anyoneinvolved in the individual's care and/or the payment therefor;“Researchers” 722, containing anyone conducting medical research; and“All Other Uses” 723, containing everyone else for any other purpose,including marketing. As shown, the corresponding settings for each ofthese groups, 724-727 respectively, is also revealed.

In a preferred embodiment, the user would have the option to click on acell, which would open arrow tab 708 and revise the selection usingpull-down list 709, as explained with respect to FIG. 7(A). As shown,whenever a selection is being modified, in an optional embodiment, amessage 728 is displayed to indicate that one or more other users haveexpressed comments about the particular selection. In one preferredembodiment, this message could indicate the number of comments 729(a)regarding a particular selection, and whether those comments tend toagree or disagree with the proposed setting, as reflected in 729(b) and729(c), respectively. Such use of ratings and comments by other users isdescribed in Applicant's prior '544 patent, to help inform suchselections.

In other fields such as telecommunications, software programming,retail, finance, entertainment, media and advertising, a number of largegroup collaboration technologies have been successfully employed toemploy the “wisdom of the crowd” to issues involving choice. The coverstory in the Jun. 20, 2005 issue of Business Week, entitled “The Powerof Us: Mass Collaboration on the Internet is Shaking Up Business,”provides a discussion of this trend toward “mass collaboration” anddescribes the trend toward using a variety of Internet-basedtechnologies to enable companies and industries to “tap into thecollective intelligence of employees, customers and outsiders.”

A number of patents have been directed to such systems of the prior art,including U.S. Pat. No. 6,189,029 to Fuerst, entitled “Web Survey ToolBuilder and Result Compiler”; U.S. Pat. No. 6,457,045 to Hanson et al,entitled “System and Method for Group Choice Making”; and U.S. Pat. No.6,801,900 to Lloyd, entitled “System and Method for Online DisputeResolution”. Additionally, those of ordinary skill in the art willrecognize that a number of technologies help enable such services. Inaddition to explicit ratings, these include collaborative filteringtechniques to generate personal recommendations based upon explicitratings, as well as “content-based” filtering techniques that extractkey concepts and automate the categorization, cross-referencing,hypertext linking and/or presentation of such information. Anothertechnology is “content mining,” which automatically analyzes text andother unstructured content to make intelligent decisions andrecommendations. And yet another technique involves the use of “implicitratings” based on specific actions of participants and which are, inturn, used to provide recommendations based on peer group categorizationbut without resorting to explicit ratings.

Well conceived implementations employing these and other relatednetwork-based technologies are broadly understood as increasinglyproviding a way “of turning self-interest into social benefit—and realeconomic value [through an] ‘architecture of participation,’ so it'seasy for people to do their own thing . . . [but where] those actionscan be pooled into something useful to many.” The June 2005 BusinessWeek article describes capabilities like the seller ratings on eBay,song ratings on Yahoo! and millions of customer-generated productreviews on Amazon.com, eOpinions.com and a multitude of similarservices—all of which, at their core, “help decide hits and duds”—asbeing examples of the power of such technologies in action.

Other than as disclosed in Applicants prior '544 patent, these sorts oftechnologies have not heretofore been proposed nor applied to the fieldof setting privacy preferences. As shown in FIG. 7(D), such facilitiescan be intuitively integrated into the user interface so as to assistindividuals looking to consider a particular action. For example, inseveral non-limiting illustrations, particular organizations, specificindividuals and/or proposed uses of data may be voted up or down basedon reputation scores. Similarly, it may be useful for individuals whoare affected by a particular disorder to designated segments of thebioinformatic data such as a gene that bears closer scrutiny by anyonewith a certain family or health history and describe the value ofopening up the information to a greater number of data seekers or onedata seeker in particular. Or in other cases, persons who are concernedabout the potential for misuse by particular groups may wish to explainthe importance of protecting certain information from being discovered.In one preferred embodiment of the invention, such crowd-sourcingtechniques respecting selections would be employed as a supplement tothe foregoing described guide recommendations, and may be turned on oroff (and/or filtered to select from whom comments are accessible) fromthe user's general preferences, or as a result of placing a check incheckbox 719.

FIG. 7(D) also illustrates that as the level of granularity increases,in one preferred embodiment, the user interface automatically createsgroups of the successively more granular selections into logical groupsunder a single columnar heading or row title. Such groups could becreated on the fly, or alternatively be pre-authored and programmed todisplay when applicable so that such groups appear and thereby helpavoid overwhelming end users. “Mixed” indicator 726 illustrates the useof such a designation to indicate that additional variability is presentwithin the more detailed settings that comprise the “Researchers”category. Clicking on this selection opens in the direction (or asapplicable, the directions) shown by arrow 717 to reveal such granularselections until they resolve to an expression for which the threeprimary preferences apply for any further granularity available in thesetting. Accordingly, should all of the underlying granularity be made asingle setting, then the display for the next higher level ofabstraction would return to whatever level was applicable to all of thegranular detail.

FIG. 7(E) illustrates the effect of selecting “Mixed” 726 in FIG. 7(D).As shown therein, row 730—which corresponds to row 720 shown in FIG.7(D)—reminds the user that the row pertains to preferences for thereferring entity and any other persons or entities that it recommends.And as shown in FIG. 7(D), the setting for everyone in this category is“Allow”, which is reflected in cell 724. Similarly, “Clinicians”, whichare reflected by 721 and corresponding “Allow” selection 725, arerepeated from FIG. 7(D). But at this deeper level of granularity, the“Researchers” heading 731 replaces the corresponding “aggregation”function provided by 721 in FIG. 7(D) and now lists at the next mostgranular level any persons or entities that comprise the (in thisillustrative case) researchers category. In one preferred embodiment,the display of granular results may be implemented using anaccordion-style user interface, were such detailed users list opens uponclicking on 721 in FIG. 7(D), and where clicking on title 731 closes thelist and returns to prior view (i.e., in this case with “Mixed”revealed). However, if the user changes all of the selections shown to“Allow” for example, then upon clicking title 731, item 726 wouldthereafter display “Allow” to indicate such uniformity of settingsbelow.

In a preferred embodiment, the settings are listed in the order fromleast granular to most granular. Thus, as shown, the first setting732(a) is for an individual researcher 732(b), and includes atraditional file tree drop down icon 732(c) in the event the user wishesto set any further granularity. In this illustrative case, the icon isshown in its closed state, because there are no more granular settings,and any uses of the information by the indicated researcher for anymedical research purpose are set to “Allow”, and thus can be representedin the aggregation thereof 733.

By way of non-limiting example, if the user had elected to approveaccess for this researcher only for a specified purpose such as aparticular clinical trial or study, then caption 733 would continue todisplay as “Allow” but by opening the file tree drop down icon, the nameof that particular study would appear as the intended purpose for suchallowed access; and if otherwise silent, then with regard to all otherresearch purposes, the next less granular setting in which suchresearcher was included as a member would apply. For example if Dr.Smith were a Researcher at Children's Hospital of [Named Place] shown asrow 734, then the setting of “Allow” indicated in 735 would apply. Thesame would be the case if she were a researcher recommended by the[Trusted Entity] 730. However, if she were not a member of either one ofthese groups, but instead included in the “Researchers recommended byany [other credible organization's] list of preferred researchers” 736,or a “Researcher serving one of the conditions listed in the user'shealth profile” 738, then “Ask Me” would apply on account of setting 737or 739, respectively.

Certain aspects of the foregoing User Interface design principles may beobserved in practice within websites currently employing Applicant'searlier teachings in this regard, including any Platform for EngagingEveryone Responsibly (or PEER) sites sponsored by Genetic Alliance as ofthe date of filing this application. However, other novel aspects,including use of the “Mixed” selections, slider-based access toincreasingly granular settings, and in relation to displaying genomicdata extend such earlier approaches to address particular requirementsfor segmented bioinformatic data as addressed herein.

FIG. 7(E) also illustrates the continued use of the “Mixed” setting 741in relation to the “All researchers” category 740, thereby showing howparticular data elements can be controlled through the user interface atincreasingly granular levels for use in accordance with the ontologyillustrated in FIG. 5. FIG. 7(F) shows the effect of clicking on “Mixed”setting 741 in the previous drawing. As shown, the file tree indicator742 is now turned in a downward direction, thereby revealing granulardetails for such things as basic demographic information 743, symptomsdata 744, diagnosis information 745, data regarding treatments 746,laboratory test results 747, genetic data 748, and psychiatricevaluation report 749. Each of these data elements is accompanied by theuser's corresponding privacy preference selection setting, 750-756.Additionally, clicking on “Add more” link 757 enables the user todesignate further data segments she wishes to establish, and the accesscontrols therefor. Persons of ordinary skill in the art will recognizethat by clicking on any of the data elements shown, the next moredetailed file tree level can be revealed, for applying or reviewing theselected privacy preference selection, and will appreciate the manner inwhich this user interface can be used to review and/or edit selectionsmade for specific genomic segments and/or metadata associated therewith,as described in relation to FIG. 2, and/or specific redactions asdescribed in relation to FIG. 2 of Applicant's '554 patent.

FIGS. 7(G) and 7(H) illustrate use of the “Mixed” setting 716 todesignate that variability exists along both axes of the improved userinterface, contrasted with the one-dimensional variability previouslydescribed in connection with FIG. 7(C). As shown, arrow 758 indicatesthat variability exists along both the horizontal and vertical sliders.In one non-limiting example, clicking on this setting results in openingthe 3-by-4 cell matrix shown in FIG. 7(H). As shown therein, the sameprinciples that have been described in relation to extending thevertical axis preferably apply with respect to expanding the horizontalaxis. While it is up to the system designer to select the best methodsfor such expression, in one preferred embodiment, similar to how slidinghandle 705(c) downward reveals logical groups of successively moregranular elements to the extent necessary to represent the user'spreferences respecting which resource seekers, preferably as defined inconnection shaded box 517 (of FIG. 5) may access particular data (ordata elements) as defined in connection with shaded box 518 for whatpurposes of use 545, so too may sliding handle 704(c) to the rightextend the types of data and accessibility types thereof in logicalgroups of successively more granular access types 548 and FIG. 7(I)hereof.

FIG. 7(H) provides one non-limiting example of such one preferredapproach. As shown, clicking on “Mixed” setting 716 (or alternativelysliding handle 704(a) to the right) initially reveals three columns asthe first logical sub-group from Total Access 706 of FIG. 7(G). Thesepertain to finding, using and exporting de-identified data, within thecolumn entitled “Anonymous Data” 759; finding, using and exportingidentifying information, within the column entitled “Identifying Data”760; and permitting use of contact information to make contact, withinthe third column entitled “Contact me” 761. Persons of ordinary skill inthe art will recognize by use of the term “de-identified data” that thispertains to complying with the standard for de-identifying data inaccordance with HIPAA or the Common Rule, and while the term “anonymous”is not used in such U.S. statutes, it is employed herein simply toconvey the essence of data that is devoid of such identifyinginformation, and may be replaced with another caption that is moreeasily understood by system users should another title prove to be moreuseful at the literacy level of the intended users. Accordingly, for thepurpose of this disclosure, “anonymous” refers to data that have beende-identified or anonymized in accordance with the law and/or otherregulations applicable to the jurisdiction where the technology isdeployed.

FIG. 7(I) provides a description of possible sub-classes for theforegoing three columnar categories. As illustrated by the class andsub-class tree indicating one optional semantic approach to definingsuch data type and accessibility type granularity spanning from thetypes with the lowest privacy-related implications to the greatest. Asshown therein, these move from “Total Access” 706, to the threesub-categories 759-761 described in relation to FIG. 7(H). In oneoptional sub-group, “Anonymous Data” 759 may be broken into twosub-classes, “Find/Analyze” 762, in which such de-identified data may beindexed, analyzed and viewed; and “Use/Export” 763, wherein suchde-identified data may be both used and exported. In turn, at the nextmost granular levels of data accessibility, deconstructing“Find/Analyze” 762 into three foundational components entailsauthorizing such anonymous information to be indexed 764; permittingsuch data to be analyzed within grouped data 765 (i.e., without everhaving row level or and separately permitting the data to be viewed (forexample in row level data extracts and/or in search results 766. Also asshown, at such next more granular level, deconstructing “Use/Export” 763is comprised of permitting use of anonymous information, entitled “Use”767; allowing so called “Limited Export” 768 focusing on only permittingthe data to be exported to another Private Access-enabled system; and“Unlimited Export” 769 of such data to another system—even if it suchsystems do not employ Private Access.

FIG. 7(I) also provides a description of optional sub-classes for“Identifying Data” 760, which may be broken into two higher levelsub-classes, “Find/Analyze” 770, in which such identifying informationmay be indexed, analyzed and viewed; and “Link/Use/Export” 771, whereinsuch identifying information may be both linked to the de-identifieddata 759, used and exported. In turn, at the next most granular levelsof data accessibility, deconstructing “Find/Analyze” 770 can be intothree foundational components. These entail authorizing such identifyinginformation to be indexed 772; permitting such data to be analyzedwithin grouped data 773 (i.e., without ever having row level or andseparately permitting the identifying data to be viewed); and allowingsuch information to be viewed 774, for example in row level dataextracts and/or in search results.

Also as shown, the higher order category “Link/Use/Export” 771 may bedeconstructed into five possible granular details. In one preferredembodiment, these include permitting the linking of the identifyinginformation with de-identified data, entitled “Permitted Linking” 775;allowing so called “Limited Use” 776, which entails usage of theidentifying information to conduct an activity but wherein no permissionis granted to disclose such identifying information in the final resultsfrom such activity; “Limited Export” 777, wherein the data may beexported to another Private Access-enabled system; “Unrestricted Use”778, wherein the identity may be revealed as part of the permitted use;and “Unrestricted Export” 779 of such identifying information to anysystem—even if it such systems do not employ Private Access.

Persons of ordinary skills in the art will appreciate that the foregoingsemantic classes and sub-classes are arbitrary and employed principallyfor illustrative purposes only, and not to restrict or artificiallylimit the scope of the invention. As such, other semantic ontologies forpurposes of use 547 and/or accessibility type 548, respectivelydescribed in relation to FIG. 5 hereof, may be employed in lieu of theforegoing in accordance with the principles hereof.

It should also be apparent that while each of the features illustratedin the accompanying drawings and the foregoing description areattractive and add to the usefulness of the invention, all of suchforegoing features are not required in order to practice the principlesof the invention and thus many are optional. Additionally, although thedisclosure hereof has been made by way of examples and description ofpreferred embodiments, it will be evident that various adaptations andmodifications may be employed without departing from the spirit andscope thereof.

A key issue in genome interpretation and ascertaining meaning forvariants of unknown significance (VUS) is attaining better access to thesubject's medical and family history, as well as associatedenvironmental factors. At present, such correlations are impeded bysignificant “silo-ing” of information, which result from a number offactors. Some of these are regulatory in nature, arising fromobligations imposed under law on data holders. Other impediments have todo with practical disincentives to sharing information, the control overwhich may produce a competitive advantage to the holder. Others arisefrom the heterogeneity of technologies and large variations in semanticrepresentations employed across the industry, which are in turnpromulgated to some degree by purpose of use, and in other cases bycompetition among hardware, software and data collection vendors.Nevertheless, in many cases, the difficulties arise from the growingrecognition that with access to enough information—even fullyde-identified data, and particularly longitudinal data—can becomeidentifying in nature.

While for illustrative purposes, the foregoing system of segmenting andcontrolling the flow of sensitive information has been describedprincipally in relation to genomic data, many of the disclosed featuresand principles will also be useful to enhancing the privacy and enablingbroad sharing of other forms of bioinformatic data and other forms ofsensitive data. For example, including survey data commonly held inregistries, clinical observations and data based on interactions withproviders commonly held in electronic health records (EHR) systems, anddata acquired through active and passive monitoring through mobiledevices and other systems designed to collect detailed data about theindividual.

All of such instances and the like (including without limitationrespecting personal educational information, financial data,e-government based information, and smart grid-based data) are expresslyincluded in the foregoing disclosures; and persons of ordinary skill inthe art will be able to extend the teachings of this disclosure to suchfurther forms of sensitive data without undue experimentation ormodification in the basic teachings. Moreover, by doing so, it will beapparent to persons of ordinary skill in the art that incorporating allof such information together with the individual's genomic data andcomprehensive longitudinal health record under a common, inherentlyconsumer-centric means of enabling greater accessibility and enhancedprivacy protection that cuts across the silos in which such raw data istoday represents extraordinary promise to realizing the optimalconditions for assuring and maintaining trust, accelerating thePrecision Medicine Initiative, and the shared benefit capable of beingderived from similar sorts of initiatives throughout the world.

The terms and expressions employed herein have been used as terms ofdescription and not of limitation; and thus, there is no intent ofexcluding equivalents, but on the contrary it is intended to cover anyand all equivalents that may be employed without departing from thespirit and scope of this disclosure.

What is claimed is:
 1. A computer implemented method for selectivelydesignating segments of bioinformatic data in an electronic document,the method comprising the steps of: (a) receiving a command by at leastone computer from a party wishing to designate such segments identifyingat least one portion of an electronic document to be subject to accesscontrol; (b) presenting, by said at least one computer, a set ofselectable access control directives defining conditions for access tosaid at least one portion of said electronic document, said selectableaccess control directives selected and controlled by the holder ofprivacy rights of said document; (c) receiving, from said party wishingto designate such segments by said at least one computer, selectableaccess control directives; and (d) imposing access control of said atleast one portion by said at least one computer in accordance with saidconditions in response to receiving said selectable access controldirectives.
 2. The method of claim 1, wherein said selectable accesscontrol directives minimally consists of designate said at least oneportion, allow access to at least one portion of said bioinformaticdata, prohibit access to said at least one portion of said bioinformaticdata, and query said holder of privacy rights of said document fordirection as to whether to allow or prohibit access thereto.
 3. Themethod of claim 1, wherein said steps of presenting a set of selectableaccess control directives comprises providing a privacy menu on adocument viewing user interface.
 4. The method of claim 3, wherein saidstep of receiving selective directives comprises receiving mouse clickson said privacy menu to identify selected directives.
 5. The method ofclaim 3, further comprising: displaying, on a user interface display bysaid computer, said privacy menu in response to said holder of privacyrights of said document hovering a mouse over said at least one portionpresented on said user interface display.
 6. A system for selectivelydesignating segments of bioinformatic data in an electronic documentcomprising: (a) at least one computer configured to receive from a partywishing to designate segments of bioinformatic data, selected directivesof a set of selectable access control directives; (b) receive a commandfrom the person to whom said bioinformatic data pertains or saidperson's designated representative designating such segments of saidelectronic document so as to identify at least one portion of saidbioinformatic data to be subject to access control; (c) present a set ofselectable access control directives defining conditions for access tosaid at least one portion of said bioinformatic data; (d) receiveselected directives of said set of selectable access control directives;and (e) impose access control of said at least one portion of saidbioinformatic data in accordance with said conditions in response toreceiving said selective access control directives.
 7. The system ofclaim 6, wherein said set of selectable access control directivesdefining conditions for access to said at least one portion of saidbioinformatic data minimally consists of allow access to at least oneportion of said bioinformatic data, prohibit access to said at least oneportion of said bioinformatic data, and query the person to whom saidbioinformatic data pertains (or that person's designated representative)for direction as to whether to allow or prohibit said proposed access.8. The system of claim 6, wherein said sat least one computer is furtherconfigured to present a privacy menu on a document viewing userinterface.
 9. The method of claim 8, wherein said at least one computeris further configured to receive mouse clicks on said privacy menu toidentify selected directives.
 10. The system of claim 6, wherein saidbioinformatic data is a genome, and said designated segments arechromosomes comprising said genome.
 11. The system of claim 10, whereinsaid bioinformatic data is metadata concerning variants identified onthe chromosomes, and said designated segments are the said metadataindicating for each of said chromosomes the name of any gene located onsaid chromosome wherein a variant is identified.
 12. The system of claim10, wherein said bioinformatic data is meta-metadata concerning whetheror not any variants are identified on the chromosomes, and saiddesignated segments are the said meta-metadata indicating in a binaryexpression for each said chromosome if there is at least one genelocated on said single chromosome wherein a variant is identified. 13.The system of claim 6, wherein said bioinformatic data is a genome, andsaid designated segments are all of the sub-bands of all of thechromosomes comprising said genome.
 14. The system of claim 13, whereinsaid bioinformatic data is metadata concerning variants identifiedwithin the sub-bands of the chromosomes, and said designated segmentsare the said metadata indicating for each of said chromosomal sub-bandthe name of any gene located within said single chromosomal sub-bandwherein a variant is identified.
 15. The system of claim 13, whereinsaid bioinformatic data is meta-metadata concerning whether or not anyvariants are identified within the sub-bands of the chromosomes, andsaid designated segments are the said meta-metadata indicating in abinary expression for each said chromosomal sub-band if there is atleast one gene located within said single chromosomal sub-band wherein avariant is identified.
 16. The system of claim 6, wherein saidbioinformatic data is a genome or exome, and said designated segmentsare all of the genes located within said genome or exome.
 17. The systemof claim 16, wherein said bioinformatic data is metadata concerningvariants identified within said genes, and said designated segments arethe said metadata indicating for each of said genes the name of anyvariants located within said genes wherein at least one variant isidentified.
 18. The system of claim 16, wherein said bioinformatic datais meta-metadata concerning whether or not any variants are identifiedwithin said genes, and said designated segments are the saidmeta-metadata indicating in a binary expression for each one of saidgenes if there is at least one variant identified
 19. The system ofclaim 6, wherein said bioinformatic data is a genome or exome, and saiddesignated segments are all of the SNPs located within said genome orexome.
 20. The system of claim 19, wherein said bioinformatic data ismetadata concerning variants identified within the base pairs comprisingsaid genome or exome, and said designated segments are the said metadataindicating for each of said SNPs any variants located within said basepairs wherein at least one variant is identified.
 21. The system ofclaim 19, wherein said bioinformatic data is meta-metadata concerningwhether or not any variants are identified within said base pairs, andsaid designated segments are the said meta-metadata indicating in abinary expression for each one of said SNPs where there is at least onevariant identified.
 22. The system of claim 6, wherein saidbioinformatic data is a genome or exome, and said designated segmentsare the genes and SNPs that are suspected to be associated with aparticular medical diagnosis, condition or disorder.
 23. The system ofclaim 22, wherein said bioinformatic data is metadata concerningvariants identified within any of said genes or SNPs that are suspectedto be associated with a particular medical diagnosis, condition ordisorder, and said designated segments are the said metadata indicatingfor each of said diagnosis, condition or disorder the name of the genesand/or SNPs that are affected and the name of any variants locatedwithin said one or more genes or SNPs wherein at least one variant isidentified.
 24. The system of claim 22, wherein said bioinformatic datais meta-metadata concerning whether or not any variants are identifiedwithin any of the genes or SNPs that are suspected to be associated witha particular medical diagnosis, condition or disorder, and saiddesignated segments are the said meta-metadata indicating in a binaryexpression for each one of said diagnosis, condition or disorder, ifthere is at least one genes or SNP where a variant is identified. 25.The system of claim 6, wherein said bioinformatic data is a genome orexome, and said designated segments are the genes and SNPs suspected tobe associated with a particular symptom, medical sign, or relevance todrug responsiveness.
 26. The system of claim 25, wherein saidbioinformatic data is metadata concerning variants identified within anyof said genes or SNPs that are suspected to be associated with aparticular symptom, medical sign, or relevance to drug responsivenessand said designated segments are the said metadata indicating for eachof said symptom, medical sign, or relevance to drug responsiveness, thename of the genes and/or SNPs that are affected and the name of anyvariants located within said one or more genes or SNPs wherein at leastone variant is identified.
 27. The system of claim 25, wherein saidbioinformatic data is meta-metadata concerning whether or not anyvariants are identified within any of the genes or SNPs that aresuspected to be associated with a particular symptom, medical sign, orrelevance to drug responsiveness, and said designated segments are thesaid meta-metadata indicating in a binary expression for each one ofsaid symptom, medical sign, or relevance to drug responsiveness, ifthere is at least one genes or SNP where a variant is identified.
 28. Anapparatus for identifying segments of bioinformatic data and associatingselectable access control directives as a step of a sequence analysispipeline on genomic data, such apparatus comprising: (a) an integratedcircuit comprising a set of hardwired digital logic circuits that areinterconnected by a plurality of physical electrical interconnects, oneor more of the plurality of physical electrical interconnects comprisingan input for receiving the plurality of reads of genomic data; (b) saidset of hardwired digital logic circuits being in a wired configurationto access an index of the one or more genetic reference sequences viaone of the plurality of physical electrical interconnects, and to mapthe plurality of reads to one or more segments of the one or moregenetic reference sequences according to said index; (c) configuring theset of hardwired digital logic circuits to extract one or morecomponents of said genetic data from the plurality of reads of geneticdata; (d) configuring the set of hardwired digital logic circuits toencrypt said one or more components; and (e) assigning a GUID to saidencrypted one or more components to generate a globally-unique addressfor each of said one or more components.
 29. The apparatus of claim 28,wherein said one or more components include all of the chromosomes, eachchromosome being assigned a GUID, and the unencrypted content of suchGUIDs collectively comprising the subject's genome or exome;
 30. Theapparatus of claim 28, wherein said one or more components include allof the regions, bands and sub-bands of all of the chromosomes, each suchregion, band and/or sub-band being assigned a GUID, and the unencryptedcontent of such GUIDs collectively comprising the subject's genome orexome;
 31. The apparatus of claim 28, wherein said one or morecomponents include all of the genes, each such gene being assigned aGUID, and the unencrypted content of such genes collectively comprisingthe subject's genome or exome;
 32. The apparatus of claim 28, whereinsaid one or more components include all of the base pairs, each suchbase pair being assigned a GUID, and the unencrypted content of suchbase pairs collectively comprising the subject's genome or exome;